notes/DC Dutta Obstetrics 10th Edition_6.txt

The vomiting is related to the pregnant state. Other causes of nausea and vomiting should be excluded. Depending upon the severity, it is classified as: (i) Simple vomiting of pregnancy  or  milder  type and  (ii)  hyperemesis gravidarum or severe type.
SIMPLE  VOMITING  (Syn:  morning  sickness,  emesis gravidarum):  The patient  complains  of  nausea  and

occasional sickness  on  rising  in the  morning.  Slight vomiting is so common in early pregnancy (about 50%) that it is considered as a symptom of pregnancy. It may, however, occur at other times of the day. The vomitus is small and clear or bile stained. It does not produce any impairment of health or restrict the  normal  activities of the women. The feature disappears with or without treatment by 12-14th week of pregnancy. High level of serum human chorionic  gonadotropin,  estrogen and altered immunological states are considered responsible for  initiation of the manifestation,  which  is probably aggravated by the neurogenic factor.
Management: Assurance is important. NVP is thought to be fetoprotective. Taking of dry toast or biscuit and avoidance of fatty and spicy foods are enough to relieve the symptoms in majority. Supplementation with vitamin
B1   100 mg daily is helpful. If the simple measures fail,
antiemetic drugs-vitamin B6  alone or in combination
with doxylamine is safe and effective. It is used as a first time therapy (ACOG). Promethazine and ondansetron can be used. Patient is advised to take plenty of fluids (2-2.5 L in 24 hours) and fruit juice.

HYPEREMESIS GRAVIDARUM (HG) DEFINITION: It is a severe type of vomiting of pregnancy which has got deleterious effect on the health of mother and/or incapacitates her in day-to-day activities. The triad of adverse effects due to protracted NVP are:  (a) >5%  loss  of  pre-pregnancy  weight,  (b)  dehydration and (c) electrolyte imbalance (RCOG-2016). The other adverse effects are: metabolic acidosis due to starvation or alkalosis due to loss of hydrochloric acid from vomiting.
INCIDENCE: There has been marked fall in the incidence during  the last 30 years.  It is now a rarity in hospital practice (less than 1  in 1,000 pregnancies).  The reasons are-(a) better application of family planning knowledge which reduces the number of unplanned pregnancies, (b)  early  visit to  the  antenatal  clinic,  and  (c)  potent antihistaminic and antiemetic drugs.
ID Chapter 15: Nausea and Vomiting in Pregnancy

ETIOLOGY: The etiology is obscure but the following are the known high-risk factors:
1.  It is mostly limited to the first trimester with a peak around 9 weeks and resolves by 20 weeks (90%).
2.  It is more common in first pregnancy, with a tendency to recur again in subsequent pregnancies (15%).
3. Younger age.
4.  Low body mass.
5.  History of motion sickness or migraine.
6.  It has got a familial history-mother and sisters also suffer from the same manifestation.
7.  Women suffered nausea and vomiting while on COCs. It is more prevalent in hydatidiform mole and multiple pregnancy.
8.  It is more common in unplanned pregnancies but much less amongst illegitimate ones.
Women with hyperemesis gravidarum,  often suffer from  transient  form  of  hyperthyroidism  (clinical  or subclinical).
THEORIES:  (1)  Hormonal:  (a)  Excess  of  chorionic gonadotropin or higher  biological  activity  of hCG is associated. This is proved by the frequency of vomiting at the peak level of hCG and also the increased association with hydatidiform mole or multiple pregnancy when the hCG titer is very much raised;  (b)  High serum level of estrogen and (c) Progesterone excess leading to relaxation of  the  cardiac  sphincter  and  simultaneous  retention of gastric fluids due to impaired gastric motility.  Other hormones involved are: thyroxine, prolactin, leptin and adrenocortical hormones.
(2) Psychogenic: It probably aggravates the nausea once  it  begins.  But  neurogenic  element  sometimes plays a role, as evidenced by its subsidence after shifting the patient from the home surroundings (biosocial).
(3)   Dietetic  deficiency:   Probably   due   to  low carbohydrate reserve, as it happens after a night without
food. Deficiency of vitamin B6,  vitamin B1  and proteins
may be the effects rather than the cause.
(4) Allergic or immunological basis. (5) Decreased gastric motility is found to cause nausea.
Whatever may be the cause of initiation of vomiting, it is probably aggravated by the neurogenic element. Unless it is not quickly rectified, features of dehydration and carbohydrate starvation supervene and a vicious cycle of nausea ➔ vomiting ➔ carbohydrate starvation ➔ ketoacidosis ➔ vomiting.
PATHOLOGY: There are no specific morbid anatomical findings. The changes in the various organs as described by  Sheehan  are  the  generalized  manifestations  of starvation and severe malnutrition.
Liver: Liver enzymes are elevated. There is centrilo­ bular fatty infiltration without necrosis.
Kidneys: Usually normal with occasional findings of fatty change in the cells of first convoluted tubule, which may be related to acidosis.

Heart: A small heart is a constant finding. There may be subendocardial hemorrhage.
Brain: Small hemorrhages in the hypothalamic region giving the manifestation of Wernicke's encephalopathy. The lesion may be related to vitamin B1  deficiency.
METABOLIC, BIOCHEMICAL AND CIRCULATORY CHANGES: The changes are due to the combined effect of dehydration and starvation consequent upon vomiting.
Metabolic:  Inadequate  intake  of  food  results  in glycogen  depletion.  For  the  energy  supply,  the  fat reserve is broken down. Due to low carbohydrate, there is  incomplete  oxidation  of  fat  and  accumulation  of ketone bodies in the blood. The acetone is ultimately excreted through the kidneys and in the breath. There is also increase in endogenous tissue protein breakdown resulting in excessive excretion of  nonprotein nitrogen in the urine. Water and electrolyte metabolism are seriously affected leading to biochemical and circulatory changes.
Biochemical:  Patients  develop  acidosis  ( due  to starvation) and alkalosis from loss of hydrochloric acid and hypokalemia. Loss of water and salts in the vomitus results in fall in plasma sodium, potassium and chlorides. Hepatic dysfunction results in ketosis with rise in blood urea and uric acid.  Patient suffers from hyponatremia, hypokalemia, raised hematocrit and ketonuria.
Circulatory: There is hemoconcentration leading to rise in hemoglobin percentage, RBC count and hematocrit values. There is slight increase in the white cell count with increase in eosinophils. There is concomitant reduction of extracellular fluid.

■ CLINICAL COURSE
From the management and prognostic point of view, the cases are grouped into:
11    Early	II   Late (moderate to severe)
The patient is usually a nullipara, in early pregnancy. The onset is insidious.
EARLY: Vomiting occurs throughout the day. Normal day­ to-day activities are curtailed. There is no evidence of dehydration or starvation.
LATE:  Evidences of dehydration  and  starvation  are present.
Symptoms: Vomiting is increased in frequency with retching. Urine quantity is diminished even to the stage of oliguria.  Epigastric pain,  constipation  may  occur. Complications  may  appear  (described  further)  if  not treated.
Signs: Features of dehydration and ketoacidosis: D1y coated tongue, sunken eyes, acetone smell in breath, tachycardia,  hypotension,  rise in temperature may be noted, jaundice is a late feature. Such late cases are rarely seen these days. Vaginal examination and/or ultraso­ nography is done to confirm the diagnosis of pregnancy.


NVP  and  HG  are  associated  with  hyponatremia, hypokalemia,  low serum urea level, raised hematocrit, ketonuria with metabolic alkalosis.  When it is severe, metabolic acidosis develops.

Investigations:
♦   Urinalysis: (1) Quantity-small,  (2) Dark color,  (3) High specific gravity with acid reaction, ( 4) Presence
of acetone, occasional presence of protein and rarely bile pigments and (5) Diminished or even absence  of chloride.
♦   Biochemical  and  circulatory  changes:  LFTs  are abnormal in many patients ( 40%) with rise in the level of serum transaminases and bilirubin. Jaundice may be present.  Routine  and periodic estimation of the serum electrolytes ( sodium, potassium and chloride) is helpful in the management of the case.
♦  Serum  TSH,  T3   and  free  T4:   Women  (60%)  may
suffer from transient phase of thyroid dysfunction (thyrotoxicosis: clinical or subclinical).
♦   Ophthalmoscopic  examination  is required  if  the patient is seriously ill. Retinal hemorrhage and detach­ ment of the retina are the most unfavorable signs.
♦   ECG when there is abnormal serum potassium level.

DIAGNOSIS: The pregnancy is to be confirmed  first. Thereafter,   all   the   associated  causes  of  vomiting (enumerated before) are to be excluded.
Ultrasonography  is  useful  not  only  to  confirm the  pregnancy  but  also  to  exclude  other,  obstetric (hydatidiform mole, multiple pregnancy), gynecological, surgical or medical causes of vomiting.
Differential diagnosis: When vomiting is persistent in  spite  of  usual  treatment  other  causes  of  severe vomiting (medical or surgical) should be considered and investigated.
COMPLICATIONS: Maternal: The majority of the clinical manifestations are due to the effects of dehydration and starvation with resultant ketoacidosis. Leaving aside those symptomatology, the following complications may occur which are fortunately rare nowadays.
1. Neurologic complications-0 Wernicke's encep­
halopathy, beriberi due to thiamine (vitamin B1)
deficiency; l) Pontine myelinolysis; 8 Peripheral neuritis;  Korsakoff's psychosis; 0 Depression.
2. Stress ulcer in stomach;
3. Esophageal  tear  and bleeding  (Mallory-Weiss syndrome);
4.  Jaundice, hepatic failure; 5.  Convulsions and coma;
6. Hypoprothrombinemia due to vitamin K deficiency; 7. Renal failure and    8. SGA.
Women with NVP/HG may need other professionals involvement such as midwives, dieticians, nutritionists including a psychiatrist.

Chapter 15: Nausea and Vomiting in Pregnancy

Effects on the fetus: Fetus usually remains unaffected once the problem is resolved. Fetal risks are due to low birth weight and preterm birth (18%).
PREVENTION: The only prevention is to impart effective management to correct simple vomiting of pregnancy.
Common measures managing nausea and vomiting in pregnancy are:
a.  To take small amount and at frequent intervals.
b. To drink fluids in between meals and not after the meals.
c.  Not to lie down immediately after meals. d. To avoid food that causes gastric irritation.
e.  To avoid food (high fat) and odors that trigger nausea and vomiting.

I MANAGEMENT
Early causes with NVP are managed at home with oral antiemetics.
The principles in the management are: ♦  Maintenance of hydration.
♦  To control vomiting.
♦  To correct the fluids and electrolytes imbalance.
♦  To correct metabolic disturbances (acidosis or alkalo-sis).
♦  To prevent the serious complications of severe vomiting. ♦   Care of pregnancy.
♦  Wernicke's encephalopathy-is  due to vitamin B (thiamine)  deficiency.  The  patients  present  with:
1
blurred vision, weakness, confusion, memory problems and  drowsiness.  Examination reveals:  nystagmus, ophthalmoplegia, hyporeflexia or ataxia. USG scan is done for pregnancy. She is treated with antiemetics,
vitamin B1 replacement and rehydration with normal saline.
Hospitalization for a woman with HG: Whenever a patient is diagnosed as a case of hyperemesis gravida­ rum, she is admitted. Surprisingly, with the same diet and drugs used at home, the patient improves rapidly.
Indications are: (a) Protracted NVP despite the use of oral antiemetics, (b) Continued NVP with ketonuria and/or weight loss >5%, (c) Presence of any comorbidity (medical/surgical).
Fluids: Oral feeding is withheld for at least 24 hours after the cessation of vomiting. During this period,  fluid is given through intravenous drip method. The amount of fluid to be infused in 24 hours is calculated as follows: Fast hydration IV therapy (1-1.5  L) with normal saline and potassium (if not contraindicated) is given. With this regime-dehydration, ketoacidosis, water and electrolyte imbalance are  likely  to be rectified.  Serum  electrolyte should  be  estimated  and  corrected  if  there  is  any abnormality. Enteral nutrition through nasogastric tube may also be given.
Drugs:  Used are-cyclizine, prochlorperazine, metoclopramide, ondansetron and corticosteroids (Table 15.2).
fl Chapter 15: Nausea and Vomiting in Pregnancy
6
Table 15.2: Recommended antiemetic therapies and dosages.

First line



Second line


Third line


•  Cyclizine SO mg PO, IM or IV 8 hourly
♦  Prochlorperazine (stemetil} 5-10 mg 6-8 hourly PO; 12.5 mg 8 hourly IM/IV; or 25 mg PR daily Promethazine 12.5-25 mg 4-8 hourly PO, IM, IV or PR
•
♦  Chlorpromazine 10-25 mg 4-6 hourly PO, IV or IM, or 50-100 mg 6-8 hourly PR
•  Metoclopramide 5-1O mg 8 hourly PO, IV or IM (maximum 5 days duration} ♦   Domperidone 1O mg 8 hourly PO; 30-60 mg 8 hourly PR
♦  Ondansetron 4-8 mg 6-8 hourly PO; 8 mg over 15 minutes 12 hourly IV
Corticosteroids: Hydrocortisone 100 mg twice daily IV and once clinical improvement occurs, convert to prednisolone 40-50 mg daily PO, the dose gradually tapered until the lowest maintenance dose that controls the symptoms is reached.

(IM: Intramuscular; IV: Intravenous; PO: By Mouth; PR: By Rectum)


(a)  Antiernetic drugs: Cyclizine, prochlorperazine, prome­ thazine are effective. Doxylamine is an effective antihistamine for nausea and vomiting ofpregnancy. Vitamin B (pyridoxine-25 mg) and doxylamine (25 mg) are also safe and effective combination. Metoclopramide stimulates gastric and intestinal motility without stimulating the secretions. It is found useful and used as a second­ line drug.
(b) Hydrocortisone: Control HG in a case with hypotension or in intractable vomiting. IV or oral method prednisolone is used in severe cases.
(c) Nutritional supplementation with vitamin B  (loo mg daily), vitamin B ,  vitamin C and vitamin B   are given. Rarely, patients may need parenteral nutritional therapy.
1
12
6
(d) Ondansetron is safe and effective and used as a second line therapy.
(e) Women with severe HG need thromboprophylaxis.
Nursing care: Sympathetic but firm handling of the patient is essential.  Social and psychological support should be extended.
■  Parenteral  thiamine  should  be  given  to  prevent Wernicke's encephalopathy.
■  The  maternal  complications  and  the  preventive measures are to be taken as below:
1.  Neurology complications are to be treated  with injection thiamine 100 mg IV daily.
2. Stress ulcer with the use of protein pump inhibitors (IV).


3. Hemoconcentration may need thromboprophylaxis with LMWH. Women admitted with hyperemesis should be given thromboprophylaxis.
■  Woman with NVP and HG need to be multidisciplinary team management involving physician, psychiatrist, nutritionist and the midwife.
Hyperemesis progress chart is helpful to assess the progress of patient while in hospital. Daily record  of pulse, temperature, blood pressure at least twice daily, intake-output, urine for acetone, protein, bile, blood bio­ chemistry and ECG (when serum potassium is abnormal) are important.
Clinical features of improvement are evidenced by: a.  Subsidence of vomiting.
b.  Feeling of hunger. c.  Better look.
d. Normalization of blood biochemistry (electrolytes). e.  Disappearance of acetone from the breath and urine. f.   Normal pulse and blood pressure.
g.  Normal urine output.
h. Normal fetal growth on follow up.
Diet: Before the intravenous fluid is omitted, the foods are  given  orally. At first,  dry carbohydrate foods like biscuits, bread and toast are given. Small but frequent feeds are recommended. Gradually full diet is restored.
Termination of pregnancy is rarely indicated. Intrac­ table hyperemesis gravidarum in spite of therapy is rare these days in India.


fi-MIH
►   Excessive vomiting of pregnancy incapacitating day-to-day activities and/or deteriorating the health of the mother is called hyperemesis gravidarum. It is rare nowadays (1 in 1,000 pregnancies}. It is common in first birth and limited to early pregnancy. The exact cause is not known. It is thought to be due to exce_ss hCG. However, once vomiting starts, probably neurogenic elements aggravate the state. The morbid pathological changes are due to starvation. High-risk factors for vomiting in pregnancy are many.
►  The clinical manifestations are due to the effect of dehydration, starvation and ketoacidosis. If not rectified promptly, the condition may turn fatal.
►   Management consists of hospitalization, sympathetic but firm handling of the patient, maintenance of hydration by IV infusion, antiemetic drugs, correction of electrolyte imbalance and supply of glucose to protect the liver and vitamin supplement. Intractable hyperemesis gravidarum in spite of therapy is rare these days. Termination of pregnancy is rarely indicated.
►   Vitamin 86 (pyridoxine-25 mg) and doxylamine (25 mg) are safe and an effective combination.


Hemorrhage in Early Pregnancy



CHAPTER



 
❖ Spontaneous Abortion (Miscarriage) ❖ Threatened Miscarriage
❖ Inevitable Miscarriage ❖ Complete Miscarriage ❖ Incomplete Miscarriage ❖ Missed Miscarriage
❖ Septic Abortion ►  Management
❖ Recurrent Miscarriage ❖ Cervical Incompetence ❖ Induction of Abortion
❖ Medical Termination of Pregnancy
(MTP)


►  Methods ofTermination of Pregnancy
►  Recommendations
►  First Trimester and Midtrimester Termination of Pregnancy
❖ Ectopic Pregnancy ► Tubal Pregnancy
►  Acute Ectopic Pregnancy ►  Unruptured Tubal Ectopic
►  Diagnosis of Ectopic Pregnancy ❖  Management of Ectopic Pregnancy
►  Interstitial ►  Abdominal


►  Ovarian ►  Cornual ►  Cervical
►  Pregnancy of Unknown Location ►  Cesarean Scar Pregnancy
►  Heterotopic Pregnancy
❖ Gestational Trophoblastic Diseases (GTD)
►  Hydatidiform Mole
►  Partial or Incomplete Mole
►  Placental Site Trophoblastic Tumor (PSTT)
►  Persistent Gestational Trophoblastic Disease




Common risks in early  pregnancy  are:  miscarriage, ectopic pregnancy and gestational trophoblastic diseases. Spontaneous abortion is the most common complication. The causes of bleeding in early pregnancy are broadly divided into two groups:
-,        y,I_  _  _ _     .. _ 1 _  •  .    11    •          .'I

approximately  at  22  weeks  (154  days)  of  gestation. The  expelled  embryo  or  fetus  is  called  abortus.  The word miscarriage is the recommended terminology for spontaneous abortion.

INCIDENCE:  The  incidence  of miscarriage is around it   75% 1f these mcy.





Title: DC Dutta's Textbook of Obstetrics, 10th  edn Name: Hiralal Konar
ERRATA
Read dosage of misoprostol in µg (microgram) instead of mg (milligram) on page numbers 157,158,166,167,168,185,322 and 390.

These will be corrected in the next print.


,bscure. al)  are

itabolic





1ges  are The  rest :ommon :ommon 1%)  and n  about of three nosome,
ID Chapter 16: Hemorrhage in Early Pregnancy

Flowchart 16.1: Classification of abortion.

ABORTION
I
I
I



Spontaneous	Induced
(miscarriage)	(deliberate)



Isolated (sporadic)	Recurrent	L(MegTaPl )	(uIlnlesgaafel ) Threatened	InevIitable	IComIplete	Incomplete     MiIssed    Septic l(less coSmepmtioc-nc)ommon
I
l






Pregnancy    of    Uncertain Viability: Intrauterine gestation sac ( <20 mm mean diameter) with  no obvious yolk sac or fetus  or  fetal  echo  less  than 6 mm crown-rump length with no obvious fetal heart activity. In order to confirm or refute viability,  a repeat  scan at a minimal interval of 1  week is necessary.



e.g., 3n = 69,  4n  = 92.  Monosomy X ( 45,X) is the single most common  chromosomal  abnormality  in  miscarriages  (20%). Structural chromosomal rearrangements are observed in 2-4% of abortuses. These include translocation, deletion, inversion and ring formation. Other chromosomal abnormalities like mosaic, double trisomy, etc., are found in about 4% of abortuses. 95% of all chromosomal abnormalities are caused by errors in maternal gametogenesis and about 5% are due to paternal errors. Triploidy is obse1ved with hydropic molar placental changes.
ENDOCRINE   AND   METABOLIC   FACTORS   (10-15%):   Luteal Phase Defect (LPD) results in early miscarriage as implantation and  placentation  are  not   supported  adequately.  Deficient progesterone secretion from corpus luteum or poor endometrial response to progesterone is the cause. Thyroid abnormalities: Overt  hypothyroidism  or  hyperthyroidism  is  associated  with increased fetal loss. Thyroid autoantibodies are often increased. Diabetes  mellitus  when  poorly  controlled  causes  increased miscarriage.

ANATOMICAL ABNORMALITIES (3-38%)
•   Ceruicouterine factors: These  are related mostly to the second trimester abortions: (1) Cervical incompetence, either congenital or acquired is one of the most common cause. (2) Congenital malformation of the uterus  in  the form  of  bicornuate  or  septate  uterus  may  be responsible for midtrimester recurrent miscarriages.   Causes  of  fetal loss are:   (i)   reduced   intrauterine  volume,   (ii)   reduced expansile   property   of   the   uterus,  (iii) reduced placental vascularity when implanted on the  septum and (iv) increased uterine irritability and contractility.  (3)  Uterine  (fibroid) especially of the submucous variety  might be responsible not only for infertility but also for  abortion. This is due to distortion or partial obliteration of  the  uterine  cavity.  Other causes  are:  decreased  vascularity  at the implantation site, red degeneration of fibroid and  increased uterine irritability. ( 4)  Intrauterine  adhesions   (synechiae)  interfere  with implantation, placentation and  fetal growth. Depending on the severity of adhesions,  e.g.,  total (Asherman's syndrome), corporal or cervicoisthmic,  patient suffers from amenorrhea, hypomenorrhea, infertility  or recurrent abortion.
INFECTIONS (5%)-are the accepted causes of late as well  as early abortions. Transplacental fetal infections occur with  most microorganisms  and  fetal  losses  could   be  caused  by any.

Infections could be-(i) Viral: Rubella, cytomegalovirus,  variola, vaccinia  or  HIV.  (ii)  Parasitic:  Toxoplasma,   malaria. (iii) Bacterial: Ureaplasma, Chlamydia, Brucella. Spirochetes hardly cause abortion before 20th week because of effective  thickness of placental barrier.

IMMUNOLOGICAL  DISORDERS  (5-10%)  (p. 588)
•   Antiphospholipid Antibody Syndrome (APAS)-is due to the presence of antiphospholipid antibodies. These are: Lupus Anticoagulant (LAC), Anticardiolipin Antibodies  (ACAs) and   -glycoprotein  1 antibodies  ( -GPl).  Mechanisms  of pregnancy  loss  in  women  with  APAS  are:  (a)  inhibition  of trophoblast   function  and  differentiation,  (b)  activation  of complement pathway, (c) release oflocal inflammatory mediators (cytokines,  interleukins) and (d) thrombosis of uteroplacental vascular    bed.   Ultimate  pathology   is   fetal  hypoxia.
•   Immune factors: Cytokines are immune molecules. Cytokine response may be either T-helper 1 (Thl) type or T-helper 2 (Th2) type. Thl response is the production of proinflammatory cytokines [interleukin-2, interferon and Tumor Necrosis Factor (TNF)]. Th2 response is the production of anti-inflammatory cytokines (interleukins-4, 6 and 10). Successful pregnancy is the result of predominantly Th2 cytokine response. Women with recurrent miscarriage have more Thi response.
•   Autoimmunity: Natural Killer (NK) cells present in peripheral blood  and  that  in  the  uterus  are  different  functionally. There  is  no  relationship  between  uterine  natural  killer (uNK) cell number and future pregnancy outcome though uNK  cells  help  trophoblast  invasion,  proliferation  and angiogenesis. Human Leukocyte Antigen (HLA) incompatibility between couples or absence of maternal blocking antibodies is not considered as the cause of recurrent miscarriage.
MATERNAL  MEDICAL  ILLNESS  (p.  246):  Cyanotic  heart  disease, hemoglobinopathies are associated with early miscarriage.
PREMATURE  RUPTURE  OF THE  MEMBRANES  inevitably  leads to abortion.
Paternal factors: Sperm chromosomal anomaly (translocation) can cause miscarriage. Some women who miscarry recurrently may have successful pregnancies following marriage with a different man.
Thrombophilias: Inherited thrombophilia (p. 161, 328,  414) causes both early and late miscarriages due to intravascular


coagulation and thrombosis. Protein C resistance (factor V Leiden mutation) is the most common cause. Other conditions are: Protein C deficiencyandhyperhomocysteinemia antithrombin III or prothrombin gene mutation.

ENVIRONMENTAL FACTORS: Conclusions relating to envi­ ronmental factors are dificult to establish.
•   Cigarette smoking-increases the risk due to formation of carboxyhemoglobin and decreased oxygen transfer to the fetus. Alcohol consumption should be avoided or minimized during pregnancy.  X-irradiation  and antineoplastic drugs are known to cause abortion. X-ray exposure up to 10 rad is oflittle risk.
•   Contraceptive agents-IUD in situ increases the risk whereas oral pills do not.
•  Drugs, chemicals, noxious agents-anesthetic gases, arsenic, aniline, lead, formaldehyde increase the risk.
•   Miscellaneous-exposure to electromagnetic radiation from Video Display Terminals (VDTs) does not increase the  risk. Women can use hair dyes, watch television and fly in airlines during pregnancy.
UNEXPLAINED  (40-60%):  In  spite  of  the  numerous  factors mentioned,  it is indeed difficult, in the majority, to pinpoint the exact cause of miscarriage. Too often, more than one factor is present. However, risk of abortion increases with increased maternal  age.  About  22%   of   all  pregnancies  detected  by serum  -hCG (peri-implantation)  are lost,  before  the clinical diagnosis.

COMMON CAUSES OF MISCARRIAGE
First trimester: (1) Genetic factors (50%), (2) Endocrine disorders  (LPD,  thyroid  abnormalities,  diabetes),  (3) Immunological disorders (autoimmune and alloimmune), (4) Infection, and (5) Unexplained.
Second  trimester:  (1)  Anatomic  abnormalities-(a) Cervical    incompetence	( congenital	or	acquired), (b) Miillerian fusion defects (bicornuate uterus, septate uterus),  (c)  Uterine synechiae,  and  (d)  Uterine  fibroid. (2) Maternal medical illness. (3) Unexplained.

MECHANISM OF MISCARRIAGE: In the early weeks, death of the ovum occurs first, followed by its expulsion.
■   Before 8 weeks: The ovum,  surrounded by the villi with the decidual coverings, is expelled out intact. Sometimes, the external os fails to dilate so that the entire mass is accommodated in the dilated cervical canal and is called cervical miscarriage (Fig. 16.lA).
■   Between 8 and  14  weeks:  Expulsion  of  the  fetus commonly  occurs  leaving  behind the  placenta  and the membranes. A part of it may be partially separated with brisk hemorrhage or remains totally attached to the uterine wall.
■   Beyond 14th week: The process of expulsion is similar to that of a  'mini  labor'.  The fetus is expelled first followed by expulsion of the placenta after a varying interval.

Chapter 16: Hemorrhage in Early Pregnancy     JD  THREATENED  MISCARRIAGE
DEFINITION: It is a clinical entity where the process of miscarriage has started but has not progressed to a state from which recovery is impossible (Fig. 16.2A).
CLINICAL FEATURES
The patient, having symptoms suggestive of pregnancy, complains of:
(1)  Bleeding per vaginam is usually slight and may be brownish or bright red in color. On rare occasion, the bleeding may be brisk,  especially in the  late  second trimester. The bleeding usually stops spontaneously.
(2)  Pain: Bleeding is usually painless but there may be mild cramps, backache or dull pain in lower abdomen. Pain appears usually following hemorrhage.
Pelvic examination  should  be  done  as  gently  as possible.  (a)  Speculum  examination  reveals-bleeding if  any,  escapes through the  external os.  Differential diagnosis  includes  ectopy,   ectopic  pregnancy  and molar pregnancy. (b) Gentle digital examination reveals the closed external os (Fig. 16.2A).  The uterine size corresponds to the period of amenorrhea. The uterus and cervix feel soft. Pelvic examination is avoided when ultrasonography  is  available  (see  below).  With time bleeding and pain subsides and pregnancy continues.
INVESTIGATIONS
Routine  investigations  include:   (1)   Blood-for hemoglobin, hematocrit, ABO and Rh grouping. Blood transfusion  may  be  required  if  abortion  becomes inevitable. Anti-D gamma globulin has to be given in Rh-negative  nonimmunized  women.   (2)  Urine  for immunological test of pregnancy is not helpful as the test remains positive for  a variable period even after the fetal death.



















Figs. 16.1A and B: (A)  Cervical  miscarriage; (Bl  Inevitable miscarriage.
ID Chapter 16: Hemorrhage in Early Pregnancy
INEVITABLE MISCARRIAGE

DEFINITION: It is the clinical type where the presence of  bleeding,  cervical  dilation  and  abdominal  pain indicates  impending  abortion  ( expulsion  of  the conceptus).
CLINICAL FEATURES:  The  patient,  having  the  features of  threatened  miscarriage,  develops  the  following manifestations:  (1)  Increased  vaginal  bleeding.  (2) Aggravation  of  pain in  the  lower  abdomen  which  may be colicky in nature. (3) Internal examination reveals dilated internal os of the cervix through which the products of conception are felt (Fig. 16.28).


Fig.  16.1C:  Ultrasonographic picture of anembryonic sac.

Ultrasonography (TVS) findings are: (1) TVS helps to confirm pregnancy, its location and viability. (2) Gestational sac is visible as early as 4-5 weeks of gestation. (3) Yolk sac is seen at 5½ weeks. (4) The embryo is seen at about 6 weeks, with presence of cardiac motion (p. 599}. With this there is 98% chance of continuation of pregnancy. (5) Anembryonic sac is diagnosed when the mean gestational sac diameter (MSD) is  25 mm and no embryo is seen on TVS. It suggests early pregnancy failure (Fig. 16.1B).
Serum  progesterone  value  of  25 ng/mL generally indicates a viable pregnancy in about 95% of cases. Serial serum hCG level is helpful to assess the fetal wellbeing. Ectopic pregnancy must be ruled out during investigations (p. 173).
TREATMENT
Rest: The patient should be in bed (pelvic rest) for few days until bleeding stops. Prolonged restriction of activity has got no therapeutic value.
There is some evidence that treatment with proges­ terone improves the outcome. Progesterone induces immunomodulation to shift the Thl (proinflammatory response) to Th2 (anti-inflammatory response). Use of hCG is not preferred.
ADVICE ON DISCHARGE: She is to be followed up with repeat sonography at 2-3 weeks of time. The following indicates unfavorable outcome: falling serum  -hCG, decreasing size of the fetus, irregular shape of the gestational sac or decreasing fetal heart rate ( <100 bpm).
PROGNOSIS:  (1) In about  two-thirds, the pregnancy continues beyond 28 weeks. (2) In the rest, it ends either as inevitable or missed miscarriage. If the pregnancy continues, there is increased risk fetal of preterm labor, placenta previa, placental abruption growth restriction and fetal anomalies.
Anembryonic sac (silent miscarriage Fig. 16.18): It is a sonographic diagnosis. There is absence of fetal pole in a gestational sac with diameter of 25 mm or more. Uterus is to be evacuated once the diagnosis made.

MANAGEMENT is aimed: (a) To accelerate the process of expulsion. (b) To maintain strict asepsis.
General  measures:  Excessive  bleeding  should be promptly  controlled  by  administering  methergine  0.2 mg or oxytocin 10 IU IM if the cervix is dilated and the size of the uterus is less than 12 weeks. The blood loss is corrected by Intravenous (IV) fluid therapy and blood transfusion.
Active treatment
■   Before 12 weeks: (1) Dilatation and evacuation followed by curettage of the uterine cavity by blunt curette using analgesia or under general anesthesia. (2) Alternatively, suction evacuation followed by curettage is done.
■   After 12 weeks: The uterine contraction is accelerated by oxytocin drip (10 units in 500 mL of normal saline) 40-60 drops per minute. If the fetus is expelled and the placenta is retained, it is removed by ovum forceps, if lying separated. If the placenta is not separated, digital separation followed by its evacuation is to be done under general anesthesia.

COMPLETE MISCARRIAGE
DEFINITION:  When the  products  of  conception are expelled en masse, it is called complete miscarriage.

CLINICAL FEATURES: There is history of expulsion of a fleshy mass per vaginam followed by: (1) Subsidence of abdominal pain. (2) Vaginal bleeding becomes trace or absent.  (3) Internal examination reveals:  (a) Uterus is smaller than the period of amenorrhea and a little firmer, (b) Cervical os is closed and (c) Bleeding is trace. (4) Examination of the expelled fleshy mass is found complete. (5) Ultrasonography (TVS): reveals empty uterine cavity.
MANAGEMENT: Transvaginal sonography is  useful to see that uterine cavity is empty, othe1wise evacuation of uterine curettage should be done.
Rh-NEGATIVE WOMEN: A Rh-negative patient without antibody in her system should be protected by anti-D gamma globulin 50 µg or 100 µg intramuscularly in cases of early miscarriage or late miscarriage respectively within 72 hours. However,  anti-D may not be required in a case
Chapter 16: Hemorrhage in Early Pregnancy     111 ..,,.















Figs. 16.2A to C: (A) Threatened miscarriage; (Bl Incomplete miscarriage: placental tissues till left behind (arrow); (C) Complete miscarriage.

with complete miscarriage before 12 weeks of gestation where no instrumentation has been done.

INCOMPLETE  MISCARRIAGE
DEFINITION: When the entire products of conception are  not  expelled,  instead  a  part  of  it  is  left  inside the uterine cavity, it is called incomplete miscarriage. This is the most common type met amongst women, hospitalized for miscarriage complications.
CLINICAL FEATURES: History of expulsion of a fleshy  mass per vaginam followed by: (1) Continuation of pain  in lower  abdomen.  (2)  Persistence  of  vaginal  bleeding. (3) Internal examination reveals-(a) uterus smaller than the period of amenorrhea, (b) patulous cervical os often admitting tip of the finger and (c) varying amount of bleeding.  ( 4) On examination,  the expelled mass is found incomplete (Fig. 16.2C). (5) Ultrasonography­ reveals heterogeneous echogenic material (products of conception) within the cavity.

COMPLICATIONS:  The  retained  products  may  cause: (a) Profuse bleeding, (b) sepsis or (c) placental polyp.
MANAGEMENT:  In  recent  cases-Evacuation  of  the Retained Products of Conception (ERPC) is done. She should be  resuscitated before any active treatment is undertaken.
■   Early  abortion:  Dilatation and evacuation under analgesia  or  general  anesthesia  is  to  be  done. Evacuation of the uterus may be done using MVA also (p. 615).
■  Late abortion: The uterus is evacuated under general anesthesia and the products are removed by ovum forceps or by blunt curette. In late cases, dilatation and curettage operation is to be done to remove the bits of tissues left behind. The removed materials are subjected to a histological examination.
Medical management of incomplete miscarriage may be done. Tablet misoprostol 200 mg is used vaginally every

4 hours. Compared to surgical method, complications (p. 165) are less with medical method.

MISSED MISCARRIAGE
DEFINITION: When the fetus is dead and retained inside the  uterus for a variable period,  it is called  missed miscarriage or early fetal demise.
PATHOLOGY: The causes of prolonged retention of the dead fetus in the uterus are not clear. The liquor amnii gets absorbed and the placenta becomes pale, thin and may be adherent. USG (TVS) diagnosis: CRL >7 mm and no cardiac motion seen; MSD >25 mm and no embryo­ an embryonic sac; collapsing gestational sac, irregular amnion and yolk sac calcification indicates embryonic demise.
CLINICAL FEATURES: The patient usually presents with features  of threatened  miscarriage followed  by:  (1) Persistence of brownish vaginal discharge. (2) Subsidence of pregnancy symptoms.  (3) Absent fetal heart sound with Doppler ultrasound. ( 4) Real-time ultrasonography reveals the absence of fetal cardiac motion and fetal movements.

COMPLICATIONS:  The  complications  of  the  missed miscarriage are those mentioned in intrauterine fetal death (Ch. 21). Blood coagulation disorders are less likely to occur in missed miscarriage.

MANAGEMENT
♦  Expectant	♦  Medical	♦  Smgical
♦  Uterus  is  less  than  12  weeks:   (i)  Expectant management:  Many women expel the conceptus spontaneously (Fig. 16.3). (ii) Medical management: Prostaglandin El (misoprostol) 800 µg vaginally in the posterior fornix is given and repeated after 24 hours if needed. Expulsion usually occurs within 48 hours. (iii) Suction evacuation or dilatation and evacuation is done either as a definitive treatment or it can be done
Im Chapter 16: Hemorrhage in Early Pregnancy
(1)  Rise   of  temperature  of  at   least   100.4°F   (38°C) for 24 hours or more,  (2) offensive or purulent vaginal discharge and (3) other evidences of pelvic infection such as lower abdominal pain and tenderness.
INCIDENCE: It is dificult to work out the overall incidence of septic abortion.  About  10% of abortions requiring admission to hospital are septic. The majority of septic abortions are associated with incomplete abortion. While in the majority of cases, the infection occurs following illegal induced abortion but infection can occur even after spontaneous abortion.









Fig.  16.3:   Decidual  cast  expelled  following  missed miscarriage.

when the medical method fails.  The risk of damage to  the  uterine  walls  and  brisk  hemorrhage  during the operation should be kept in mind.
♦  Uterus more than 12 wee/cs: Induction of abortion is done by the following methods:
Prostaglandins are more effective than oxytocin in such cases. The methods used are:
■   Combined regimen  of  200 mg mifepristone PO, followed by 800 mg misoprostol by any route (buccal, vaginal  or  sublingual)  is  effective.  Alternative regimen:  800  mg  of  prostaglandin  El  analog (misoprostol) tablet is used by any route (buccal, vaginal or sublingual.
■   Oxytocin-10-20 units  of oxytocin in 500 mL of normal saline at 30 drops/min is started. If fails, escalating dose of oxytocin to the maximum of 200 units may be used with monitoring.
■   Following  medical  treatment,  ultrasonography should be done to document empty uterine cavity. Otherwise Evacuation of the Retained Products of Conception (ERPC) should be done.
■   Dilatation and evacuation is done once the cervix
becomes soft with use of PGE1.  Otherwise cervical
canal is dilated using  the mechanical dilators  or by laminaria tent (p. 524). Evacuation of the uterine cavity is done thereafter slowly.

MODE OF INFECTION: The microorganisms involved in the sepsis are usually those normally present in the vagina (endogenous). The microorgaisms are: (a) Anaerobic­ Bacteroides  group  (Jragilis),  anaerobic  Streptococci, Clostridium welchii and tetanus bacillus. (b) Aerobic­ Escherichia  coli  (E.  coli),  Klebsiella,  Staphylococcus, Pseudomonas and group A beta-hemolytic Streptococcus (usually exogenous), Methicillin-Resistant Staphylococcus aureus  (MRSA).  Mixed  (polymicrobial)  infection  is more  common.  The  increased  association  of  sepsis in  unsafe  induced  abortion  is  due  to  the  fact  that: (1)  Proper  antiseptic  and  asepsis are  not taken,  (2) incomplete evacuation and (3) inadvertent injury to the genital organs and adjacent structures,  particularly the bowels.

PATHOLOGY:  In  the  majority  (80%),  the organisms are of  endogenous  origin  and the infection  is localized  to the  conceptus  without  any  myometrial  involvement. In  about  15%,  the infection either produces localized endomyometritis surrounded by a protective leukocytic barrier,  or  spreads  to  the parametrium,  tubes,  ovaries or pelvic peritoneum. In about 5%, there is generalized peritonitis and/or endotoxic shock.
CLINICAL FEATURES: Depending upon the severity and the extent of infection, the clinical picture varies widely. History of unsafe  termination by an unauthorized person is mostly concealed (Box 16.1).

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11    Temperature: >38°C.
■   Chills and rigors (suggest bacteremia).
11    Persistent tachycardia 2'90 bpm (spreading infection). ■   Hypothermia (endotoxic shock) <36°C.
11   Abdominal or chest pain.
11   Tachypnea (RR) >20/min.

SEPTIC  ABORTION	11    Impaired mental state.

DEFINITION:  Any abortion  associated  with  clinical evidences of infection  of the uterus and its contents is called septic abortion. Although clinical criteria vary, abortion is usually considered septic when there are:

11   Diarrhea and/or vomiting.
a    Renal angle tenderness.
11    Pelvic  examination:  Offensive,   purulent   vaginal  discharge, uterine tenderness, boggy feel in the POD (pelvic abscess).
Chapter 16: Hemorrhage in Early Pregnancy     -


CLINICAL GRADING: Grade I: The infection is localized in the uterus. Grade II: The infection spreads beyond the uterus to the parametrium, tubes and ovaries or pelvic peritoneum. Grade III: Generalized peritonitis and/or endotoxic shock or jaundice or acute renal failure.
Grade I is the most common and is usually associated with spontaneous abortion. Grade III is almost always associated with illegal induced abortion.
INVESTIGATIONS:  Routine  investigations   include: (I) Cervical or high vaginal swab is talcen prior to internal examination for-(a) culture in aerobic and anaerobic media to find out the dominant microorganisms,  (b) sensitivity of the microorganisms to antibiotics and ( c) smear for Gram stain. Gram-negative organisms are­ E.  coli,  Pseudomonas,  Bacteroides,  etc.  Gram-positive organisms are-Staphylococci, anaerobic Streptococci, group A beta-hemolytic, Streptococci, MRSA, Cl. welchii, Cl.  tetani,  etc. (2) Blood for hemoglobin  estimation, total and differential count of white cells, ABO and Rh grouping. (3) Urine analysis including culture.
Special investigations: (1) Ultrasonography of pelvis and abdomen to  detect  intrauterine retained products of conception, physometra, foreign body-intrauterine or intra-abdominal, free fluid in the peritoneal cavity or in the pouch of Douglas  (pelvic abscess).  (2)  Blood­ (a) Culture-if associated with spell of chills and rigors; (b) Serum electrolytes, C-Reactive Protein (CRP}, serum lactate-as an adjunct to the management protocol of endotoxic  shock.  Serum  lactate   4 mmol/L indicates tissue  hypoperfusion  and  (c)  Coagulation  profile.  (3) Plain   X-ray-(a)   Abdomen-in   suspected   cases  of bowel  injury,  (b)  Chest-for  cases  with  pulmonary complications (atelectasis).
COMPLICATIONS
Immediate: Most of the fatal complications are associated with illegally induced abortions of grade III type.
■   Hemorrhage related due to abortion process and also due to the injury inflicted during the interference.
■   Injury may occur to the uterus and also to the adjacent structures particularly the bowels.
■   Spread  of  infection  leads  to:  (a)   Generalized peritonitis-the infection reaches through:  (i) the uterine tubes, (ii) perforation of the uterus, (iii) bursting of the microabscess in the uterine wall and (iv) injury to the gut. (b) Endotoxic shock-mostly due to E. coli or Cl. welchii infection. (c) Acute renal failure-multiple factors are involved producing patchy cortical necrosis or acute tubular necrosis. It is common in infection with Cl.  welchii.  Lungs: atelectasis, ARDS (p. 574). {d) Thrombophlebitis.
All  these  lead  to  increased  maternal  deaths,  the magnitude of which is to the extent of about 20-25% as per hospital statistics.


Remote:  The  remote  complications  include:  (a) chronic debility,  (b) chronic pelvic pain and backache, (c) dyspareunia,  (d) ectopic pregnancy, (e) secondary infertility  due  to  tubal  blockage  and  (f)  emotional depression.
PREVENTION:   (1)   To   boost   up   family  planning acceptance in order to curb the unwanted pregnancies. (2) Rigid enforcement of legalized abortion in practice and   to  curb  the  prevalence  of  unsafe  abortions. Education, motivation and extension of the facilities are sine qua non to get the real benefit out of it. (3) To take antiseptic and aseptic precautions either during internal examination or during operation in spontaneous abortion.

I MANAGEMENT
GENERAL MANAGEMENT
♦   Hospitalization  is  essential  for  all  cases  of  septic abortion. The patient is kept in isolation.
♦    To take high vaginal or cervical swab for culture, drug sensitivity test and Gram stain.
♦   Vaginal examination is done to note the state of the abortion process and extension of the infection.
♦    Overall assessment of the  case  and the patient  is leveled in accordance with the clinical grading.
♦   Investigation protocols as outlined before are done.
♦    Principles  of  management  are:   (a)   To  control sepsis. (b) To remove the source of infection. (c) To give supportive therapy to bring back the normal homeostatic and cellular metabolism. (d) To assess the response of treatment.
GRADEi
Drugs: (1) Antibiotics (see below). (2) Analgesics and sedatives, as required, are given. Blood transfusion is given to improve anemia and body resistance.
Evacuation  of  the  uterus:  As  abortion  is  often incomplete,  evacuation  should  be performed  at  a convenient time within 24 hours following antibiotic therapy.  Excessive  bleeding is,  of course,  an urgent indication  for  evacuation.  Early  emptying  not  only minimizes the risk of hemorrhage but also removes the nidus of infection. The procedure should be gentle to avoid injury to the uterus.
GRADE II: Drugs: Antibiotics-mixed infections including gram-positive, gram-negative,  aerobic and anaerobic organisms are common. Ideal antibiotic regimens should cover all of them.
Antimicrobial  therapy:  A  combination  of  either piperacillin-tazobactam or carbapenem plus clindamycin (IV} gives broadest range of microbial coverage. Emperical therapy is started  first  and  is  changed  when  culture sensitivity report is available.
m Chapter 16: Hemorrhage in Early Pregnancy
♦    Piperacillin-tazobactam and carbapenems: Covers most organisms except MRSA, and are not nephrotoxic. Piperacillin-tazobactam  does  not  cover  Extended Spectrum  -Lactamase (ESBL) producers.
♦   Vancomycin or teicoplanin may be added for MRSA resistant to clindamycin.




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♦   Cardiovascular	 Persistent hypotension, persistently raised serum lactate ( 4 mmol/L).
♦   Respiratory	 Pulmonary edema, ARDS, mechanical venti-lation, airway protection.
♦   Renal failure	Renal dialysis.



♦    Gentamicin:  (3-5 mg/kg-single dose) can be given when renal function is normal.
♦    Clindamycin: Covers most streptococci, staphylococci including MRSA and is not nephrotoxic.


♦   Neurological ♦   Miscellaneous
•  Coagulation


Impaired consciousness.
Multiorgan failure, hypothermia, acidosis. t Microvascular thrombus formation.



♦    Co-amoxiclav-does not cover MRSA, Pseudomonas or ESBL-producing organisms.
♦       Metronidazole-covers anaerobes.
Analgesic,  and ATS are given as in grade  I.  Blood transfusion is more often needed than in grade I cases.
Clinical  monitoring:  To  note  pulse,  respiration, temperature, urinary output and progress of the pain, tenderness and mass in lower abdomen, CVP greater than 8mmHg.
Surgery: (1) Evacuation of the uterus-should be done early following an initial dose of antibiotics. (2) Posterior colpotomy-when the infection is localized in the pouch of Douglas, pelvic abscess is formed. It is evidenced by spiky rise of temperature, rectal tenesmus (frequent loose stool mixed with mucus) and boggy mass felt through the posterior fornix. Posterior colpotomy and drainage of the pus relieve the symptoms and improve the general outlook of the patient.
GRADE Ill
Antibiotics  are  used  as  discussed  above.  Clinical monitoring  is  to  be  conducted  as  outlined  in  grade II. Supportive therapy is directed to treat generalized peritonitis by gastric suction and intravenous crystalloids infusion. Management of endotoxic shock or renal failure, if  present,  is  to  be  conducted  as  described in  the  Ch. 38.  Features  of  organ  dysfunction  should  be carefully guarded against. Patient may  need  intensive care unit management (Boxes 16.2 and 16.3).
Laparotomy:  Indications  are-(1)  Injury  to  the uterus.(2)  Suspected  injury  to  bowel.  (3) Presence of foreign body in the abdomen as evidenced by the sonography  or  X-ray  or  felt  through  the  fornix  on bimanual examination. (4)  Unresponsive  peritonitis



11    Persistent hypotension (SBP <90 mm Hg). 11   Oliguria.
11    Serum creatinine >44.2 µmol/L.
a    Coagulation abnormalities (INR > 1.5). a    Thrombocytopenia.
11    Hyperbilirubinemia.
11    Pa02: <40 kPa.
a    Serum lactate:  4.0 mmol/L.  }  Tissue hypoperfusion.


suggestive  of  collection  of  pus.  (5)  Septic  shock  or oliguria not responding to the conservative treatment. (6) Uterus too big to be safely evacuated vaginally.
The laparotomy  should be done by experienced surgeon with a sldlled anesthetist. Removal of the uterus should be done irrespective of parity. Adnexa is to be removed or preserved according to the pathology found. Thorough inspection of the gut and omentum for evidence of any injury is mandatory. Even when nothing is found on laparotomy, simple drainage of the pus is effective.

UNSAFE  ABORTION  is  defined  as  the  procedure  of termination of unwanted pregnancy either by persons lacking the necessary skills or in an environment lacking the minimal standards or both.  About  90%  of unsafe abortions are in the developing countries comprising 13% of all maternal deaths (WHO).
All the complications (p. 159) are preventable if it is performed safely with proper postabortion care services (p. 525).

RECURRENT  MISCARRIAGE

DEFINITION: Recurrent miscarriage is defined as the sequence  of  two  or  more  spontaneous  abortions  as documented by either sonography or on histopathology, before 20 weeks (ASRM-2013). However, earlier definition (RCOG, ESHRE) states prior three or more miscarriages before 24 weeks of gestation (Table 16.l).
INCIDENCE:  This  distressing  problem  is  affecting approximately 1% of all women of reproductive age. The risk increases with each successive abortion reaching over 30% after three consecutive losses.
I ETIOLOGY

The causes of recurrent abortion are complex and most often obscure. Parental chromosomal abnormalities are the most common cause for perimplantation as well as the early pregnancy loss.
FIRSTTRIMESTER ABORTION
n  Genetic  factors  (3-8%):  Parental  chromosomal abnormalities   is   a   proven   cause   of   recurrent
[7
Chapter 16: Hemorrhage in Early Pregnancy    -    --

'fable 16.1: Types of miscarriages, diagnostic features and the manage:nent outlines.


Types
Threatened (Fig. 16.2A)


Inevitable (Fig. 16.28)


Incomplete (Fig. 16.28)

Complete (Fig. 16.2C)

Missed

Septic


Symptoms
11      Vaginal bleeding present. II      Pelvic pain

11      Vaginal bleeding present. II      Pelvic pain

11  Vaginal bleeding(may be heavy).

11     Vaginal bleeding-trace or absent.

11     Vaginal bleeding-trace, brownish in color.

11      Vaginal discharge-purulent, foul smelling with features of sepsis.


Uterine size
11     Corresponds to gestational age.

11  Sameor smaller


11     Smaller


II      Smaller

11  Smaller

11  Variable, may be larger.

Cervix (externalos}

11      Closed


II    Open with palpable conceptus

II      Open


II      Closed

11      Closed

" Open


Ultrasonography
II      Fetus alive
II      Retroplacental hemorrhage+.

II      Fetus often dead II      Retroplacenta
hemorrhage+.
II      Echogenic products of conception partly retained.

II      Uterine cavity empty.

II      Blighted ovum or fetus without cardiac activity.

II      Echogenic products of conception retained, presence of foreign body(±), free fluid in the peritoneal cavity/POD.


Management
II      Conservative management.

II      Resuscitation of the patient followed by evacuation.

II      Evacuation of the uterus.

II      No active intervention.

II       Evacuation of the uterus.

■  Antibiotics and evacuation of the uterus to remove the septic focus.




miscarriage.  The most common abnormality is a balanced   translocation.   Risk  of  miscarriage  in couples with  a balanced translocation is greater than 25%. However, the chance of a successful pregnancy even  without  treatment  is 40-50%.  Less common findings are chromosome insertion, deletions and inversions. The most common aneuploidy found are the trisomies. Trisomic miscarriage does not increase the risk in next pregnancy.
11    Endocrine and  metabolic:  0    Poorly controlled diabetic patients  do  have  an  increased  incidence of early pregnancy failure.  @   Presence of thyroid autoantibodies is often associated with an increased risk. @ Untreated hypothy1:oidism increased the risk of miscarriage  women  should be  euthyroid  before pregnancy.  8   Luteal Phase Defect (LPD) with less production of progesterone is too often related but whether the diminished progesterone level is the cause or effect is not clear  (p.  163).  0   Polycystic Ovary Syndrome  (PCOS)-exact  mechanism of increased miscarriage  is  not  known.  Besides  elevated  serum LH levels,  the other factors responsible are:  insulin resistance, hyperinsulinemia and hyperandrogenemia or hyperhomocystinemia.
11    Hyperprolactinemia: An association by competing with the HPO axis resulting insuficient folliculogenesis, oocyte maturation and LPD. Dopamine agonist may improve the outcomes.
11    Infection:  Infection  with  bacterial  vaginosis  is  a risk factor. No infection have clearly been linked to recurrent miscarriage.


11    Acquired thrombophilia with hypercoagulable states to cause various arterial thrombosis.
11    Immune factors (10-15%).
Autoimmunity:  Presence of autoantibodies causes rejection of early  pregnancy  (15%)  in  the  second trimesters mainly. Antibodies are: antinuclear antibodies, anti-DNA antibodies (double or single stranded) and antiphospholipid antibodies (p. 154, 161).
Antiphospholipid    antibody-positive    women demonstrate a tendency to miscarry at progressively lower gestational ages. Antiphospholipid antibodies are: lupus anticoagulant, anticardiolipin antibodies and anti-13  glycoprotein-I.  Causes of miscarriage are:  (a) inhibition of trophoblast proliferation and function, (b) release of local inflammatory mediators (cytokines) through complement pathway, (c) spiral artery and placental intervillous thrombosis and (d) decidual vasculopathy with fibrinoid  necrosis  (for details, p. 310).
11    Inherited thrombophilia causes both early and late miscarriages  due  to  intravascular  (spiral  artery), and  placental  intervillous thrombosis.  Protein  C resistance  (factor V  Leiden  mutation) is the most common cause. Protein C is the natural inhibitor of coagulation. Other factors are-deficiencies of protein C, S and antithrombin III. Hyperhomocystinemia and prothrombin gene mutation are also the known causes of recurrent miscarriage.
11    Unexplained:  In the  majority,  the  cause  remains unknown.
ID Chapter 16: Hemorrhage in Early Pregnancy

SECOND TRIMESTER MISCARRIAGE Common causes are:
Anatomic  abnormalities  are  responsible  for  10-15% of recurrent abortion. The causes may be congenital or acquired.   Congenital  anomalies  may  be  due  to defects in the Miillerian duct fusion or resorption (e.g., unicornuate,  bicornuate,  septate  or  double  uterus). Congenital  cervical  incompetence  is  rare.  Acquired anomalies are: intrauterine adhesions, uterine fibroids and  endometriosis  and  cervical  incompetence.  The pathology of abortion has been discussed.
Defective Miillerian fusion-such as double uterus, septate or bicornuate uterus (Figs.  16.4A and B). The association is about 12% cases of recurrent abortion. Abortions  tend  to  recur  beyond  12  weeks  and  the successive pregnancies are carried longer. Implantation on   the   septum  leads  to  defective  placentation. The  diagnosis  is  confirmed  either  by  USG  (TVS), hysterography,  MRI  or  hysteroscopy  combined  with laparoscopy in nonpregnant state.
Case history (Fig.  l6.4C): The patient had three consecutive midtrimester abortions. Hysterography revealed bicornuate  uterus.  Metroplasty  was done. Pregnancy occurred 1 year later, which was delivered by cesarean section at 39 weeks.

OTHER CAUSES OF SECOND TRIMESTER MISCARRIAGE
♦   Chronic  maternal illness-such  as  uncontrolled diabetes  with  arteriosclerotic  changes,  hemoglo-










Figs. 16.4A and B: Diagrammatic representation of-{A) septate and {Bl double uterus with  double cervix and septate vagina.













Fig. 16.4C: Hysterosalpingography showing bicornuate uterus.


binopathies, chronic renal disease. Inflammatory bowel disease, Systemic Lupus Erythematosus (SLE).
♦  Infection-syphilis, toxoplasmosis and listeriosis may be responsible in some cases.
♦    Unexplained.

CERVICAL INCOMPETENCE (CERVICAL INSUFFICIENCY)

Causes: The retentive power of the cervix (internal os) may  be  impaired  functionally  and/or  anatomically due	to the following conditions: (a) Congenital uterine anomalies.   (b)   Acquired  (iatrogenic)-common, following:  (i)  D and C operation,  (ii)  induced abortion by D  and  E   (10%),   (iii)   vaginal  operative  delivery through an undilated cervix and (iv) amputation of the cervix or cone biopsy, trachelectomy or loop excision of the cervix. (c) Others-multiple gestations, prior preterm birth. Cervical incompetence is considered as a biological continuum of spontaneous preterm birth syndrome.
DIAGNOSIS OF CERVICAL INCOMPETENCE
11    History:  Recurrent  midtrimester painless cervical dilatation  (without apparent cause) and escape of liquor amnii followed by painless expulsion of the products of conception are very much suggestive.
11    Pelvic  examination:  Interconceptional  period­ bimanual examination reveals presence of unilateral or bilateral tear and/or gaping of the cervix up to the internal os.
11      Ultrasonography(see below).
INVESTIGATIONS
Interconceptional  period:  (i) Passage number 6-8 Hegar  dilator  beyond  the  internal  os  without  any resistance and pain and absence of internal os snap on its withdrawal specially in premenstrual period indicate incompetence.
(ii)  Premenstrual  hysterocervicography  shows funnel-shaped shadow (Figs. 16.5A and B). The internal os is supposed to be tight due to action of progesterone during this phase of cycle. Similar funnel-shaped shadow may be found if hysterography is done in the proliferative phase even with a competent cervix.
(iii)  During pregnancy-(A) Clinical (speculum): Painless  cervical  shortening   and   dilatation.   (B) Sonography: Short cervix <25 mm;  funneling of the internal os >l cm. (C) Incompetent cervix may appear: (i) Y shaped, (ii) V shaped (Fig. 16.5C) or (iii) U shaped (Fig.  l6.7C). (D) Speculum examination: Detection of dilatation of internal os with herniation of the membranes (Figs. 16.5D, and  16.6A and B).

INVESTIGATIONS FOR RECURRENT MISCARRIAGE

A thorough medical, surgical and obstetric history with meticulous clinical examination should be  carried out
Chapter 16: Hemorrhage in Early Pregnancy     IIL-










Figs.  16.SA  to  E:  Diagnosis  of  the  incompetent  cervix:  (A)  Incompetent  cervix  showing  funneling   (schematic)  (Y  shaped); (Bl  Ultrasonographic view  of  normally  competent  cervix  (T shaped)';  (Cl  Ultrasonographic view  of incompetent  cervix  showing funneling (V shaped); (D) Ultrasonographic view of incompetent cervix showing funneling (U shaped); (El USG of a normal cervix in pregnancy.  Cervical  length-as  measured.
(FW: Funnel Width; FL: Funnel Length; CL: Cervical Length)


to find out the possible causes as mentioned previously. Careful history-taking  should  include-(i)  The nature of  previous  abortion  process.   (ii)   Histology  of  the placenta  or  karyotyping  of  the  conceptus,  if  available. (iii) Any chronic illness.
Diagnostic  tests:  (1)  Blood-glucose  (fasting  and postprandial), VDRL, thyroid function test, ABO and Rh grouping  (husband  and  wife),  toxoplasma  antibodies IgG  and  IgM.   (2)  Autoimmune  screening-lupus anticoagulant and anticardiolipin antibodies. (3) Serum
LH  on Dz1D3   of  the  cycle.  ( 4)  Ultrasonography-to detect congenital malformation of uterus,  polycystic
ovaries    and uterine fibroid. (5) Hysterosalpingography in the secretory phase to detect-cervical incompetence, uterine synechiae and uterine malformation. (6) This is supported by hysteroscopy and/or laparoscopy or MRI. (7) Karyotyping (husband and wife). (8) Endocervical swab to detect chlamydia, mycoplasma and bacterial vaginosis.

I TREATMENT
INTERCONCEPTIONAL PERIOD
11    To alleviate anxiety and to improve the psychology­ While counseling the couple, they should be assured that even after  three consecutive miscarriages,  the chance  of a successful pregnancy is high  (70%). However, the success rate depends on the underlying etiology as well as the age of the woman.
11    Hysteroscopic  resection of uterine septa,  syn­ echiae and submucous myomas improves the pregnancy outcome. Uterine unification operation (metroplasty) is done for cases with bicornuate uterus.
11    Chromosomal    anomalies-if    chromosomal abnormality is detected in the couples or in the abortus (unbalanced translocation),  genetic  counseling is undertaken. Couples with chromosomal translocations or  inversion  are  counseled  for  Preimplantation Genetic Diagnosis (PGD). If the defect is paternal, artificial insemination by a donor is advised.  For a maternal defect donor egg may be fertilized by the

husband's sperm. PGD is also available for parents who wish to use their own gametes.
11    Women with PCOS are best treated for their insulin resistance, hyperinsulinemia and hyperandrogenemia. Metformin therapy is helpful.
11    Endocrine  dysfunction:  Control  of  diabetes  and thyroid disorders is done (p. 265, 273).  Subclinical diabetes and/or thyroid disease may be treated when no other factor is present.
11    Genital tract  infections  are  treated appropriately following culture of cervical and vaginal discharge. Empirical treatment with doxycycline or erythromycin is cost-effective.
DURING PREGNANCY
♦   Reassurance and Tender Loving Care (TLC) are very much helpful.  Probably this removes the stress and improves uterine blood flow.
♦   Ultrasound  should   be   used  at   the  earliest  to detect a viable pregnancy. This will influence further management.  If the fetus is viable ultrasonogra­ phically at 8-9 weeks, only 2-3% are lost thereafter and similarly fetal loss is only 1 % after 16 weeks of viable fetus.
♦   Rest-patient should take adequate rest and to avoid strenuous activities, intercourse and traveling.
♦   Progesterone  therapy in  cases  with  luteal phase defect  and  recurrent  miscarriage  is  given  with natural    micronized	progesterone    100	mg daily  as vaginal suppository. It is started 2 days after ovulation. Once pregnancy is confirmed, progesterone supplementation is continued until 10-12 weeks of gestation.  Progesterone is necessary for successful implantation  and  continuation  of  pregnancy.   This is  due  to its immunomodulatory role.  It induces pregnancy  protective  shift  from  proinflammatory Thl  cytokine  response  to  a  more  favorable  anti­ inflammatory  Th2  cytokine  response.  Benefits of  hCG  therapy  in  recurrent  miscarriage  are  not established. hCG stimulates corpus luteum to produce progesterone.
mJ Chapter 16: Hemorrhage in Early Pregnancy
treated. During pregnancy, specific management is continued.
♦    Unexplained: Despite different investigations, about 40-60% of recurrent miscarriages remain unexplained. However,  'Tender Loving Care' (TLC) and some supportive therapy improves the pregnancy outcome by 70%.

I MANAGEMENT OF CERVICAL INCOMPETENCE



Figs.  16.6A  and  B:  Principles  of  encerclage  operation:   (A) Competent cervix; (B)  Incompetent cervix with herniation of the membranes.

♦    Antiphospholipid Antibody Syndrome (APS): Women are treated  with  low-dose aspirin (80 mg/day) and heparin (5,000 units SC twice daily) up to 34 weeks. Unfractionated heparin and  Low  Molecular Weight Heparin (LMWH) are equally effective and safe.
♦    Cerclage operation (Figs. 16.6A and B) for cervical incompetence is to be performed (described further).
♦    Chromosomal errors: If the defect is paternal, artificial insemination by a donor is the option. For a maternal defect donor egg may be fertilized by the husband's sperm.  PGD is also available for  parents who  wish to use their  own  gametes.  Preimplantation genetic diagnosis in blastomere stage is another option. Only then the few balanced embryos are transferred and there is successful pregnancy.
♦    Immunotherapy: Any form of immunotherapy is no longer used.
♦    Inherited thrombophilias: Antithrombotic therapy improves the  pregnancy  outcome.  Heparin  (5,000 IU SC twice daily) or low molecular weight heparin
(enoxaprin)  SC once daily  (preferred) is effective. Heparin is given up to 34 weeks.
♦    Medical complications in pregnancy: Hemoglobino­ pathies,  SLE,  cyanotic  heart  disease  are  advised to  delay  pregnancy  until  the  disease is  optimally

Cerclage operation: Two types of operation are in current use during pregnancy each claiming an equal success rate of about 80-90%. The operations are named after Shirodkar (1955) and McDonald (1963).
Principle: The procedure reinforces the weak cervix by a nonabsorbable tape, placed around the cervix at the level of internal os.
Time of operation: In a proven case, prophylactic cerclage should be done around 14 weeks of pregnancy or at least 2 weeks earlier than the lowest period of previous wastage, as early as the 10th week. Emergency (rescue) cerclage can be done when the cervix is dilated and there is bulging of the membranes. Case selection:  Cerclage operation is done mainly in cases where careful history and physical examination suggest cervical incompetence (history indicated cerclage) as it remains a diagnosis of exclusion.  Clinical  observation  is  supported  with sonographically detected short cervical length ( <25 mm), with or without funneling of the internal os (ultrasound indicated  cerclage).  Prior  to  operation,  fetal  growth and  anomaly  (aneuploidy)  scan  should   be  done  by sonography.
STEPS OF SHIRODKAR'S OPERATION  (Figs.  16.7A to C)
Step I: The patient is put under light general anesthesia and placed in lithotomy position with good exposure of the cervix by a posterior vaginal speculum. The lips of the cervix are pulled down by sponge holding forceps or Allis tissue  forceps.
Step II: A transverse incision is made anteriorly below the base of the bladder on the vaginal wall and the bladder is pushed




Vaginal mucosa

transverse incision






Anterior lip of cervix

Posterior incision




Figs. 16.7A to C: Cerclage operation:  (A)  McDonald's technique;  (B) Shirodkar's technique; (C)  Competency restored  after  encerclage  operation.
Chapter 16: Hemorrhage in Early Pregnancy     1D

up to expose the level of the internal os. A vertical incision is made posteriorly on the cervicovaginal junction.
Step III: The nonabsorbable suture material-Mersilene (Dacron) or Ethibond tape is passed submucously with the help of an aneurysm needle or cervical needle so as to bring the suture ends through the posterior incision.
Step IV: The ends of the tapes are tied up posteriorly by a reef knot. The bulging membranes, if present, must be gently reduced  beforehand into  the  uterine  cavity.  The  anterior and posterior incisions are repaired by interrupted stitches using chromic catgut.
McDONALD'S OPERATION (Figs. 16.7A to C)
The   nonabsorbable   suture   (Mersilene)   material   is
placed as a purse-string suture as high as possible (level of  internal  os)  at  the  junction  of  the  rugose  vaginal epithelium and  the smooth vaginal part of  the cervix below the level of the bladder.  The suture starts at the anterior wall of  the cervix.  Taking successive deep bites (4-5 sites), it is carried around the lateral and posterior walls back to the anterior wall again where the two ends of the suture are tied.
The operation is simple having less blood loss, and has got a good success rate. There is less formation of cervical scar and hence less chance of cervical dystocia during labor.
Postoperative  care:  (1)   The  patient   should  be in bed for at least 2-3  days.  (2)  Weekly injections  of l7a-hydroxyprogesterone caproate 500 mg IM are given in women  with  history  of prior  preterm delivery.  (3) Isoxsuprine (tocolytics) 10 mg tablet may be given thrice daily to avoid uterine irritability.
Advice on discharge: (a) Usual antenatal advice.  (b) To avoid intercourse.  (c) To avoid rough journey.  (d) To report if  there  is  vaginal  bleeding  or  abdominal  pain. (e) Periodic ultrasonographic monitoring of the fetus and the cervix.
Removal of stitch:  The  stitch  should  be  removed at 37th week or earlier if labor pain starts or features of


abortion appear.  If the stitch is not cut in time, uterine rupture or cervical tear may occur.  If the stitch is cut prior to the onset of labor,  it is  preferable to  cut it in operation theater as there is increased chance of cord prolapse especially in the cases with floating head.
Contraindications  of cerclage operation:  (i) Intrauterine   infection.   (ii)   Ruptured   membranes. (iii)  Presence of vaginal bleeding.  (iv) Severe uterine irritability. (v)  Cervical dilatation greater than 4 cm. (vi) Fetal death or defect.
Complications:   (i)    Slipping   or   cutting   through the suture.  (ii)  Chorioamnionitis.  (iii)  Rupture of the membranes.  (iv)  Abortion/preterm  labor.  (v)  Cervical lacerations during  delivery.  (vi)  Cervical  scarring  and dystocia requiring cesarean delivery.
Abdominal cerclage: A Mersilene tape is placed at the level  of the isthmus between the uterine wall and the uterine vessels.  The tape is tied anteriorly. This is done between 11 and 13  weeks following laparotomy, laparoscopy, or robotic surgery. Disadvantages are: (i) Increased complications during operation. (ii) Subsequent laparotomy for delivery or removal of the tape (if needed). (iii) Suture may be left in place for future pregnancy. Indications are-cases where cervix is hypoplastic or where prior vaginal cerclage has failed. A similar procedure can be done laparoscopically during the nonpregnant state.
Alternative to cervical cerclage-(nonsurgical) may be bed rest alone to avoid pressure on the cervix. Injection of 17a-hydroxyprogesterone caproate 500 mg IM weekly is  given  as  cervical  incompetence  is  considered  as  a continuum of preterm  birth  syndrome.  Use  of vaginal pessary,  when  cervix  is found  short  on  ultrasound,  is found helpful.
I PROGNOSIS OF RECURRENT MISCARRIAGE

The prognosis of recurrent miscarriage is not so gloomy as it was previously thought. The overall risk of recurrent miscarriage is about 25-30% irrespective of the number of
previous spontaneous miscarriage. The overall prognosis




>  Common causes of recurrent miscarriage are: (a) Genetic, (b) Metabolic (uncontrolled diabetes) and endocrine (thyroid dysfunction, PCOS), (c) Infection, (d) Thrombophilia, (e) Immunological, and (f) Unexplained and (g) Cervical incompetence.
►  Sonographic diagnostic criteria for cervical insufficiency (Cl) is: (a) Cervical length <25 mm (mid-trimester sonography) and funnelling of the internal os > 1 cm. (b) History of recurrent painless mid-trimester abortion or preterm birth (<34 weeks).
►  Cervical incompetence is primarily a clinical diagnosis. It is manifested with recurrent painless cervical dilatation and spontaneous mid­ trimester miscarriage. Premenstrual hysterocervicographic diagnosis: Funnel shape of the internal OS and the cervical canal. USG diagnosis (during second trimester of pregnancy): Short cervix <25 mm length and funneling of the internal Os> 1 cm.
>  Cervical incompetence is the ultimate manifestation of cervical weakness. It may either be due to the primary anatomic defect of the cervix or due to trauma or may be due to the complex pathology of infection or inflammation of decidua/membranes leading to uterine contractions and cervical ripening.
>  A combination of all the factors may be present in few cases. The pathological process of spontaneous mid-trimester loss and preterm birth may be continuous and is known as spontaneous preterm birth syndrome.
>  Cervical cerclage may be done based on the patient's history (history indicated) or repeated ultrasound observation (ultrasound indicated) or on physical examination. It may be done as a prophylactic, therapeutic or as an emergency (emergent cerclage) procedure.
►  Cervical cerclage is done at around 14 weeks pregnancy and the stitch is removed generally after 36 completed weeks. >  There are few contraindications and complications of cervical cerclage operations.
'--•--·ID Chapter 16: Hemorrhage in Early Pregnancy

is good even without therapy. The chance of successful pregnancy is about 70-80% with an effective therapy. Reassurance and  tender  loving care are very much helpful.

INDUCTION  OF  ABORTION

Deliberate termination of pregnancy either by medical or by surgical method before the viability of the fetus is called induction of abortion. The induced abortion may be legal or illegal (criminal). There are many countries in the globe where the abortion is not yet legalized. In India, the abortion was legalized by 'Medical Termination of Pregnancy Act' of 1971, and has been enforced in the year April 1972. The provisions of the act have been revised in 1975 and again (MTP amendment) in 2021.

MEDICAL TERMINATION OF PREGNANCY (MTP)

Since  legalization  of  abortion  in  India,  deliberate induction of abortion by a registered medical practitioner is permitted under the MTP Act. This is in the interest of mother's health and life. The following provisions are laid down:
In practice,  the following are  the indications for termination under the MTP Act:
♦    To save the life of the mother ( therapeutic or medical termination): The indications are very limited  these days:  (i)  Cardiac  diseases  (grades  III  and  IV); {ii) Psychiatric illness with the advice of a psychiatrist; {iii) Cervical or breast malignancy.
♦  Social indications: This is almost the sole indication 'to prevent grave injury to the physical and mental health of the pregnant woman  In about 80%, it is limited to parous women having unplanned pregnancy. Pregnancy caused by rape, unwanted pregnancy due to failure of contraceptive measures, are the majority in this category (20%).
♦  Eugenic: The indication is uncommon. Causes are:
(i) Structural (anencephaly), chromosomal (Down's syndrome) or genetic (cystic fibrosis) abnormalities of the fetus. {ii) When the fetus is likely to be deformed due to action of teratogenic drugs (warfarin) or radiation exposure (>10  rad)  in  early pregnancy.  {iii)  Rubella, a  viral infection affecting in  the  first  trimester,  is  an indication for termination.
EXTENSION  OF  INDICATION:  {i)  In  order  to  save  the life of the pregnant woman. (ii) In order to prevent grave injury to the physical and mental health of the pregnant woman. (iii) In view of the substantial risk that if the child was born it would suffer from a mental abnormalities as to be seriously handicapped. {iv) As the pregnancy has occurred as a result of failure of any contraceptive device by the married woman or her husband for the purpose of limiting the number of children.

SPECIAL  CATEGORY OF WOMEN FOR  MTP  UP TO 24 WEEKS:
a.  Survivors of sexual assault or rape or incest.
b.  Minors.
c.  Change of marital status during the ongoing pregnancy (widowhood and divorce).
d. Women  with  physical  disabilities  (major  disability as per criteria laid down  under  the Rights  of Pers Disabilities Act, 2016 (49 of 2016)].
e.  Mentally ill women including mental retardation.
f.   The fetal malformation that has substantial risk of being incompatible with life or if the child is born it may suffer from such physical or mental abnormalities to be seriously handicapped.
g. Women with pregnancy inhumanitarian settings or disaster or emergency situations as declared by the Government.
METHODS OF MEDICAL TERMINATION OF PREGNANCY (MTP) (Various regimens as used):
First trimester (up to 12 weeks)
11    Mifepristone and misoprostol (PGE1).
■  Mifepristone 200-600 mg orally followed in 48 hours by: Misoprostol 200-600 mg orally or 400-800 mg bucally, sublingually or vaginally (Fig. 16.8).
m  Misoprostol (PGEl)-alone 800 mg sublingually or vaginally every 3 hours for 3 doses.
11    Methotrexate and misoprostol. 11    Letrozole and misoprostol.
Letrozole  10  mg  PO  daily  for  3  days  followed  by misoprostol 800 mg sublingually on 4th day.
Surgical
11    Vacuum aspiration (MVA/EVA).
11    Suction evacuation and/or curettage. 11    Dilatation and evacuation:
e  Rapid method.
•  Slow method (Laminaria tent).
Second trimester (:; 14 weeks)
11     Mifepristone and misoprostol (PGE1).












Buccal	Sublingual
Fig. 16,8: Buccal and sublingual routes of  misoprostol administration.
Chapter 16: Hemorrhage in Early Pregnancy     ID

Mifepristone 200 mg orally; followed in 24-28 hours by misoprostol 400 mg vaginally or buccally every 3 hours up to 5 doses.
11    Misoprostol alone (PGE1).
PGE1  misoprostol,  600-800 mg vaginally followed by 400 mg  vaginally or buccally every 3 hours up to 5
doses.
a  Letrozol and misoprostol (see above).
Dinoprostone-20    mg    vaginal    suppository    eve1y 4 hours.
11    Concentrated oxytocin: 50 units oxytocin in 500 mL of normal saline infused during 3 hr, then 1 hr diuresis (no oxytocin) ➔ escalate sequentially in a similar fashion through 150, 200, 250 and 300 units oxytocin each in 500 mL normal saline.
Second trimester ( > 14 weeks)
11    Surgical abortion:  Cervical priming using medical method alone (Mifepristone + Misoprostol) or with osmotic dilator or a combination of both. This followed by Dilatation and Evacuation (D&E).

RECOMMENDATIONS WITH AMENDMENTS TO MTP ACT 2021

Confidentiality  is  to  be  strictly  maintained.  Upper gestation limit is increased from 20 to 24 weeks for the special categories of women.
The condition, failure of contraception is applied to unmarried women also.
Pregnancy  termination  can  be applied anytime during  pregnancy   for   cases  of  substantial  fetal abnormalities, as diagnosed and decided by the Medical Board.
•   In the revised rules, a Registered Medical Practitioner (RMP) is qualified to perform a MTP provided: (a) One has assisted in at least 25 MTPs in an authorized center and having  a certificate.  (b)  One has got  6 months house surgeon training in Obstetrics and Gynecology. (c) One has got diploma or degree in Obstetrics and Gynecology.
•  Termination  can  only  be  performed  in hospitals, established or maintained by the Government or places approved by the Government.
•   Pregnancy  can  only  be  terminated on  the  written consent  of  the  woman.  Husband's  consent  is  not required.
•   Pregnancy in a minor girl (below the age of 18 years) or lunatic cannot be terminated without written consent of the parents or legal guardian.
•   Termination   is   permitted   up   to  24  weeks   of pregnancy.  Opinion  of  one  Registered  Medical Practitioner (RMP) for MTP up to 20 weeks is needed.
•   Pregnancy beyond 20 weeks needs opinions of two
RMPs.


•   The abortion has to be performed confidentially and to be reported to the Director of Health Services of the State in the prescribed form.

FIRST TRIMESTER TERMINATION OF PREGNANCY (UP TO 12 WEEKS)
MEDICAL METHODS  OF  FIRST  TRIMESTER  ABORTION: Mifepristone (RU-486) and misoprostol: Mifepristone an analog of progestin (norethindrone) acts as an antagonist, blocking the effect of natural progesterone. Addition of
low-dose prostaglandins (PGE1) improves the efficiency of first trimester abortion. It is effective up to 63 days and
is highly successful when used within 49 days of gestation.
PROTOCOL:  200 mg of  mifepristone  orally  is given on
day 1.  On day 3, misoprostol (PGE1) 400 mg orally or 800 mg vaginally is given. Patient remains in the clinic for
4 hours during which expulsion of the conceptus (95%) often occurs. Patient is re-examined after 10-14 days. Complete abortion is observed in 95%, incomplete in about 2% of cases and about 1 % do not respond at all. Oral mifepristone 200mg (I tablet) with vaginal  misoprostol 800 µg ( 4 tablet, 200 µg each) after 6-48  hours is equally effective. This combipack (1 + 4) is approved by DGHS, Government of India for MTP up to 63 days of pregnancy. Medical methods are safe, effective, noninvasive and have minimal or no complications.
Methotrexate and misoprostol: Methotrexate 50 mg/m2 IM (before 56 days of gestation) followed by 7 days later misoprostol 800 mg vaginally is highly effective. Misoprostol may have to be repeated after 24 hours if it fails. If the procedure fails, ultrasound examination is done  to confirm the failure.  Then  suction evacuation should be done.
Contraindications: Mifepristone should not be used in women aged over 35 years, heavy smokers and those on long-term corticosteroid.
SURGICAL METHODS OF FIRST TRIMESTER ABORTION
■  VACUUM ASPIRATION (MVA/EVA) is done up to 12 weeks with minimal cervical dilatation. It is performed as an outpatient procedure using a plastic disposable cannula  (up  to  12  mm  size)  and  a  60  mL  plastic (double valve) syringe (Fig. 42.21). It is quicker (15 minutes), effective (98-100%), less traumatic and safer than dilatation, evacuation and curettage.
■  SUCTION  EVACUATION  AND/OR   CURETTAGE: This improvised method consists of a suction machine fitted with a cannula either plastic (Karman) or metal available in various sizes (for details of the procedure Ch. 37)
Advantages:  (1) It is done as an outdoor procedure. (2) Hazards of general anesthesia are absent as it is done, at best, under paracervical block anesthesia. (3) Ideal for termination for therapeutic indications.  (4) Blood loss is minimal.  (5) Chance of uterine perforation is much less with the plastic cannula.
r

=•--  i1 Chapter 16: Hemorrhage in Early Pregnancy
0

Drawbacks: (1) The method is not suitable with bigger size uterus of more than 10 weeks as chance of retained products is more. (2) Requires electricity to operate and the machine is costly.
11    DILATATION AND EVACUATION •  Rapid method  •  Slow method
•  Rapid method: This can be done as an outdoor procedure with diazepam sedation and paracervical block anesthesia.  The details are described in Ch.37.
Advantages: (I) As it can be done as an outdoor procedure, the patient can go home after the sedative effect is over. (2) Chance of sepsis is minimal. Drawbacks: (1) Chance of cervical injury is more. (2)  Uterus should not be more than 6-8 weeks of pregnancy. (3) All the drawbacks ofD&E (p. 525).
•  Slow method: Slow dilatation of the cervix is achieved by inserting laminaria tents (hygroscopic osmotic dilators) into the cervical canal (synthetic dilators likeDilapan, Lamicel are also used). This is followed by evacuation of the uterus after 12 hours. Vaginal
misoprostol (PGE1) 400 mg 3 hours before surgery is
equally effective for cervical ripening. The details are described on page 525.
Advantages: (1) Chance of cervical injury is minimal. (2) Suitable in cases of therapeutic indications.
Drawbacks: (1) Hospitalization is required at least for 1 day. (2) Chance of introducing sepsis. (3) All the complications of D & E (p. 525).

MIDTRIMESTER TERMINATION OF PREGNANCY (13-24 WEEKS)
MEDICAL METHODS
PROSTAGLANDINS: Prostaglandins and their analogs are very much effective. They are used extensively, especially in the second trimester. They act on the cervix and the uterus. The PGE (misoprostol, dinoprostone, gemeprost), analogs are commonly used. PGEs are preferred as they have more selective action on the myometrium and less side effects.
(i)  Misoprostol  (PGE    analog):  600-800  mg  of misoprostol is given vaginally. This is followed by 400 mg vaginally or buccally, at an interval of 3-4 hours. This is most effective as the bioavailability is high. This regimen has got 100% success in second trimester abortion. The mean induction-abortion interval is 11-12 hours.
1
(ii) Mifepristone and misoprostol: Mifepristone 200 mg oral, followed 36-48 hours later by misoprostol 800 mg vaginal, then misoprostol 400 mg oral every 3 hours for four doses is used.  Success rate of abortion is 97% and median induction delivery interval is  6.5  hours.


Pretreatment with mifepristone reduces the induction­ abortion  interval  significantly  compared  to  use  of misoprostol alone.
• Doses of  mifepristone 200 mg versus  600 mg  are similarly effective.
•  PGE1: Oral route is less effective.
Side effects are: Nausea and vomiting and diarrhea. Sublingual route has more side effects than vaginal route.
(iii)  Dinoprostone  (PGE2   analog):  20 mg is used
as a vaginal suppository every 3-4 hours (maximum for 4-6 doses). When used along with osmotic dilators, the
mean induction to abortion interval is 17 hours. PGE2 is
thermolabile (needs refrigeration) and is expensive.
OXYTOCIN: High-dose oxytocin as a single agent can be used for second trimester abortion.

SURGICAL METHODS
It  is  difficult  to  terminate  pregnancy  in  the  second trimester with reasonable safety as in first trimester. The following surgical methods may be employed.
Between 14 and 24 weeks
•  Dilatation and evacuation in the midtrimester (14-24 weeks) is less commonly done. In all midtrimester abortion,  cervical preparation must be used (WHO 2022)  to  make  the  process  easy  and  safe.  Wide mechanical  cervical dilatation is  needed  for  DIE. Inadequate dilatation causes cervical trauma, uterine perforation, more hemorrhage and retained products of conception. Cervical softening measures are helpful. Intracervical tent (hygroscopic dilators) or misoprostol can be used 400 mg vaginally or buccally 3-4 hours prior  to D/E.  Use  of  mifepristone  given  48  hours before misoprostol created more cervical dilatation. Perioperative  antibiotic  prophylaxis  as  in  the  first trimester procedure: Doxycycline 100 mg orally 1 hour before and 200 mg orally after 2 hours of the procedure is given.
The  procedure  may  need  to  be  performed  under ultrasound guidance to reduce the risk of complications. Simultaneous use of oxytocin infusion is useful.
Sonography during D/E can be used in a selective case. Following adequate cervical dilatation the amniotic sac is punctured and the fluid is drawn using an 11 to 16 mm suction cannula. The fetus is extracted in parts. After removal of the fetus, a large bore cannula is used to remove the placenta and the remaining tissue. The major complications are: uterine perforation, cervical laceration, uterine bleeding and postabortion infection.
Others are: Amniotic fluid embolism, DIC. Some women who seek sterilization, may be done at the same time by minilaparotomy procedure.
' Chapter 16: Hemorrhage in Early Pregnancy    1ml


First trimester surgical abortion offers higher eficacy  (96-100%) than medical abortion (83-98%).
HYSTEROTOMY:  The  operation is performed  through abdominal route. It rarely done these days. The steps are described in Ch. 37.
Indications: It is less commonly done  these  days. (i) Prior failed medical Termination of Pregnancy (TOP) (ii) Cases where D&E cannot be safely done: (a) fibroid in  the  lower  uterine  segment,  (b)  uterine  anomalies, (c) patients with repeated scarred uterus with placenta accreta or percreta. The operation should be combined with sterilization operation.
Complications:  Immediate:  (i)  Hemorrhage  and shock. {ii) Anesthetic complications. (iii) Peritonitis. (iv) Intestinal obstruction.
Remote:   (1)   Menstrual   abnormalities.   (2)   Scar endometriosis (1%). (3) Incisional hernia. ( 4) If pregnancy occurs, chance of scar rupture.
Rh-NEGATIVE  WOMEN:  In  nonimmunized  women, intramuscular   administration   of   100   mg   anti-D immunoglobulin is given within 72 hours of abortion.

I COMPLICATIONS OF MTP

Complications are much less (5%) if termination is done before 8 weeks by MVA or suction evacuation/curette. The complications are about five times more in midtrimester termination. Use of PG analogs and mifepristone has made second trimester MTP effective and safe. The complications are   either   related   to   the   methods   employed   or   to the abortion process.
IMMEDIATE:  (1)  Injury  to  the  cervix  (cervical  lace­ rations).  (2)  Uterine  perforation  during  D&E.  (3) Hemorrhage  and  shock  due  to  trauma,  incomplete abortion,  atonic uterus or rarely coagulation  failure. ( 4)  Thrombosis or  embolism.  (5) Postabortal triad of pain, bleeding and low-grade fever due to retained clots or products. Antibiotics should be continued, may need repeat  evacuation.  (6)  Related to the methods employed:

•  Prostaglandins-intractable vomiting, diarrhea, fever, uterine pain and cervicouterine injury.
•   Oxytocin-water intoxication and rarely convulsions. •  Hysterotomy
REMOTE: The complications are grouped into: •   Gynecological  •  Obstetrical
o   Gynecological complications include-(a) menstrual
disturbances,  (b)  chronic pelvic inflammation,  (c) infertility due to cornual block, (d) scar endometriosis (1 %) and (e) uterine synechiae leading to secondary amenorrhea.
•   Obstetrical complications include-(a)  recurrent midtrimester abortion due to cervical incompetence, (b) ectopic pregnancy (three-fold increase), (c) preterm labor,  (d)  dysmaturity,  (e)  increased  perinatal  loss, (f)   rupture   uterus,   (g)   Rh-isoimmunization   in Rh-negative women, if not prophylactically protected with immunoglobulin and  (h)  failed  abortion and continued pregnancy.
The following condition to be kept in mind when no chronic villi are found on tissue examination. Conditions are:  (a)  Failed procedure;  (b)  Incomplete procedure; Uterine malformation; or (d) Ectopic pregnancy.
Contraception: Contraceptive advice is needed following a MTP either by medical or a surgical method to prevent an unplanned pregnancy. Ovulation resumes by 3 weeks' time in majority. An IUCD may be inserted after the procedure. Other measures that can be used are: COCs, progesterone only methods (DMPA). Permanent method of tubectomy can be done at the same time by laparotomy or laparoscopy.
MORTALITY:  First  trimester: The  maternal  death  is lowest (about 0.6/100,000 procedures) in first trimester termination, especially with MVA and suction evacuation. Concurrent tubectomy even by abdominal route doubles the mortality rate.
Midtrimester:The mortality rate increases five to six times to that of first trimester. Contrary to the result of the advanced countries, the mortality from saline method has been found much higher in India compared to termination
by abdominal hysterotomy with tubectomy.


fi-,mH
►  Methods of termination of pregnancy are specific for first trimester (up to 12 weeks) and the second trimester (13-24 weeks). Medical methods are safe, effective, noninvasive and have no/minimal complications.
►  Complications of MTP are less when done before 8 weeks. The complications may be due to abortion process itself or due to the method related.
►  Complications of MTP may be immediate (hemorrhage, uterine perforation) or remote. Remote complications may be gynecological (abnormal uterine bleeding, infection, infertility) or obstetrical (ectopic pregnancy, recurrent mid-trimester miscarriages).
ID Chapter 16: Hemorrhage in Early Pregnancy
!]
_
a
!]
·
!_
.
,.-,
♦   Smoking increases the risk of ectopic pregnancy. Smoking affects cilia and smooth muscle function in the fallopian tube.
ECTOPIC  PREGNANCY
Ectopic pregnancy contributes to the cause	♦   Iatrogenic:
of maternal mortality and morbidity in the first	I.   Contraception failure:  Women  using  any  form  of
trimester of pregnancy. It accounts for 4-10% of	:;. 	contraception there is reduced risk of ectopic pregnancy.
all pregnancy related deaths. There has been   !]  	But in selected contraception failure, there is increased
about four-fold increase in incidence over the	incidence of ectopic pregnancy.
a.  IUD: It prevents intrauterine pregnancy effectively,
last couple of decades.
Recognition   of  high-risk  cases   (p.  171),   early	tubal implantation to a lesseriextenttand the ovarian
pregnancy not at all.
There   s rela ive increase in
)
diagnosis (before rupture   with the use of TVS, serum	tubal pregnancy (7 times more) should pregnancy  -hCG and laparoscopy have significantly improved the	occur with IUD in situ. CuT 380A and levonorgestrel management and outcome  of ectopic pregnancy.	devices have got the lowest rate of ectopic.

DEFINITION: An ectopic pregnancy is one in which the fertilized ovum (blastocyst) is implanted and develops outside the normal endometrial cavity.
SITES OF IMPLANATION: Flowchart 16.2.

I TUBAL PREGNANCY
FREQUENCY:  The  incidence  has  increased. The  reasons  are:  increased  prevalence  of chronic  pelvic inflammatory disease,  tubal plastic  operations,   ovulation   induction
and	IUD	use.	Secondly	early	diagnosis helps to detect some cases, that in the past, may have resolved spontaneously. Early diagnosis and therapy   have helped to reduce maternal deaths due to ectopic pregnancy. The incidence varies from 1 in 300 to 1 in 150 deliveries.
ETIOLOGY (Box 16.4)
♦   Salpingitis and Pelvic Inflammatory Disease (PIO) increases the risk of ectopic pregnancy by six-fold to ten-fold. (a) Loss of cilia of the lining epithelium and impairment of muscular peristalsis. (b) Narrowing of the tubal lumen. (c) Formation of pockets due to adhesions between  mucosa!  folds.  (d) Peritubal adhesions resulting in kinking and angulation of the tube. Chlamydia trachomatis infection is the most common risk factor. Salpingitis isthmica nodosa also increases the risk.

b  Sterilization  operation:  There  is  15-50%  chance of  being  ectopic  if  pregnancy occurs.  This  is due to sterilization failure. The risk is highest following laparoscopic bipolar coagulation.
c  Use  of progestin  only  pill or  postcoital  estrogen preparations increases the chance of tubal pregnancy probably by impaired tubal motility.
II.  Tubal  surgery: Tubal reconstructive surgery to imp­ rove   fertility,  increases  the  risk  of  tubal  pregnancy significantly. Pre-existing tubal pathology, impaired tubal motility, kinking of the tube or terminal stricture are the contributing factors.
III. Intrapelvic adhesions following pelvic surgery.
IV. ART: Tubal pregnancy is increased following ovulation induction and IVF-ET and GIFT procedures. The risk  of ectopic is 5-7% and that of heterotypic pregnancy is 1% in contrast to 1 in 5,000 in spontaneous pregnancy.
V.  Others:
♦  Previous ectopic pregnancy: There is 10-15% chances ofrepeat ectopic pregnancy.
♦   Prior induced abortion  significantly increases the risk.
♦   Developmental defects of the tube:  (a)  Elongation. (b) Diverticulum. (c) Accessory ostia.
♦  Transperitoneal migration of the ovum-contra­ lateral presence of corpus luteum is noticed in tubal pregnancy in about 10% cases.


Flowchart 16.2:  Ectopic pregnancy according to site of implantation.

SITES OF IMPLANTATION


Extra uterine	Uterine (1.5%)



Tubal
(most common 97%)


Ovarian
(0.5%)

Abdominal (1%)	Cervical (<1%)	Angular	Cornual	Cesarean
scar (<1 %)



l
Ampulla
(55%)



Isthmus
I
(25%)

I
lnfundibulum
(18%)



Interstitial
(2%)


Primary	Secondary
I
(rare)



Intraperitoneal
(common)


Extraperitoneal
broad ligament (rare)



11   History of PID.
o   History of tubal ligation.
11   Contraception failure.
11   Previous ectopic pregnancy. 11   Tubal reconstructive surgery. D   History of infertility.
11   ART particularly if the tubes are patent but damaged.
11  IUD use.
11   Previous induced abortion.
11   Tubal endometriosis.

Factors facilitating nidation in the tube:  (i) Early resumption of the trophoblastic activity is probably due to premature degeneration of the zona pellucida. (ii) Increased decidual reaction. (iii) Tubal endometriosis.
The  reasons  for  rising  incidence  of  ectopic pregnancies  are-{i)  Rise  in  the  incidence  of  STis and salpingitis. {ii) Rise in the incidence of pregnancy following ART procedures. {iii) Increased tubal surgery (either  sterilization  or  tuboplasty  procedure).  {iv) Early detection of cases that were otherwise destined to undergo spontaneous absorption.

I MORBID ANATOMY
CHANGES  IN THE TUBE:   0	Implantation in the tube occurs more commonly in intercolumnar fashion, i.e., in between  two  mucosa!  folds.   @     Decidual  change  at the site of implantation is minimal. The muscles undergo limited hyperplasia and hypertrophy but more stretching. Blood vessels are engorged. @    The blastocyst burrows through   the   mucous   membrane   and   lies   between the  lumen  and  the  peritoneal  covering-so-called intramuscular  implantation.  e   A  pseudocapsule  is formed  consisting  of  fibrin,   lining  epithelium  and few  muscle  fibers. 0 Blood  vessels  are  eroded  by  the chorionic  villi  and  blood  accumulates  in  between  the blastocyst    and    the   serous    coat. 0 The  tube   on  the implantation site is distended and the wall is thinned out. @  Blood may spill from the fimbriated end and may cause hemoperitoneum. @  The  stretching  of  the  peritoneum over  the  site  of  implantation  results  in  episodic  pain. Finally, tubal rupture occurs when the muscles and the serosa  are  maximally  stretched  and  undergo  necrosis. 0 Hemoperitoneum  is  found  in  all  cases  of  ruptured tubal ectopic  pregnancy.  ®  The  trophoblasts  of  ectopic pregnancy  do  not  usually  grow  as  that  of  a  normal pregnancy. As  a result,  hCG  production is inadequate compared to a normal pregnancy.
CHANGES  IN  THE   UTERUS:  Under  the  influence  of estrogen, progesterone from corpus luteum and chorionic gonadotropin, there is varying amount of  enlargement of the uterus with increased vascularity. The decidua develops  all  the  characteristics  of  intrauterine pregnancy    except    that    it   contains    no    evidence of horionic  villi.  When  progesterone  level  falls  due  to

Chapter 16: Hemorrhage in Early Pregnancy

fall in the level of hCG, endometrial growth is no longer maintained. Endometrium sloughs out causing uterine bleeding. Sometimes entire decidua is expelled as a single piece through the cervix. This is known as decidual cast that may be confused with a spontaneous abortion.

I MODES OF TERMINATION

The modes of termination of tubal ectopic pregnancy are as follows:
Tubal mole (Fig.  16.9):  Repeated small hemorrhages occur in the choriocapsular space, separating the villi from their attachments. The fate of the mole is either­ (a) complete absorption or {b) expulsion through the abdominal ostium as tubal  abortion  with a variable amount  of  internal  hemorrhage.  The  encysted  blood so collected in the pouch of Douglas is called pelvic hematocele.
Tubal abortion (Fig. 16.9): This is the common mode of termination if implantation occurs in the ampulla or infundibulum. Muscular contraction enhances separation and facilitates its expulsion through the abdominal ostium.
Tubal  rupture:  It  is  predominantly  common  in isthmic and interstitial implantation. As the isthmic portion is narrow and the wall is less distensible,  the wall may be easily eroded by the chorionic villi. Isthmic rupture usually occurs at 6-8 weeks, the ampullary one at 8-12 weeks and the interstitial one at about 12-16 weeks.
The  thick  myometrium  at  interstitial  zone  allows expansion for the ectopic to grow. Rupture of ectopic pregnancy results in massive hemorrhage as it is site of anastomosis for both uterine and ovarian vessels.
Depending  upon  the  site  of  mpture,  it is  known as:  (1) Intraperitoneal rupture:  This type of rupture is common. The rent is situated on the roof or sides of the tube. The bleeding is intraperitoneal. (2) Extraperitoneal rupture (intraligamentary): This is rare and occurs when the rent  lies on the  floor  of the  tube  where the broad ligament  is attached. It  is  commonly  met  in  isthmic implantation.
Secondary abdominal pregnancy: The prerequisites for   the   continuation  of  fetal   growth  outside   the tube are:  (1)  Perforation  of  the  tubal  wall  should  be a slow process. (2) Amnion must be intact. (3) Placental chorion should  escape  injury  from  the  rupture.  (4) Herniation of the amniotic sac with the living embryo and the placenta  should  occur  through  the  rent.  (5) Placenta gets attached to the neighboring structures and new vascular connection should be re-established. The fibrin is deposited over the exposed amnion to constitute a secondary amniotic sac. (6) Intestine, omentum and adjacent structures get adherent to the secondary sac (Box 16.5).
Im Chapter 16: Hemorrhage i_n Early Pregnancy


♦    Death of the blastocyst ➔ complete absorption.
♦   Massive   intraperitoneal   hemorrhage   due   to   placental separation.
♦    Infection ➔ fistulous communication with intestine, bladder, umbilicus.
♦    Fetal   death   ➔     mummification,   suppuration,   adipocere formation, calcification (/ithopedion).
♦    Continue  to  term  pregnancy  (rare-1.0%)  (risk  of  fetal malformation and deformation).

Secondary  broad  ligament  pregnancy:  Rarely pregnancy  may  continue  in  the  same  process as in abdominal pregnancy between the two layers of the peritoneum.
Arias-Stella reaction: This is characterized by a typical adenomatous change of the endotnetrial glands. Intraluminal budding together  with  typical  cell  changes  (Joss  of polarity of cells, pleomorphism, hyperchromatic nuclei, vacuolated cytoplasm and  occasional  mitosis)  are  collectively  referred to  as Arias-Stella reaction. This is strikingly due to progesterone influence. It is present in about  10-15%  cases of ectopic pregnancy. It is not, however, specific for ectopic pregnancy but rather the blightening of conceptus either intrauterine or extrauterine.
Cause of vaginal bleeding: Levels of progesterone secreted by the corpus luteum fall as there is insufficient level of hCG. Endometrial growth and function is no longer  maintained  and  if  then  sloughs  out.  On rare occasion,  the bleeding may be  due to  tubal abortion through the uterine ostium in interstitial pregnancy.
I CLINICAL FEATURES OF ECTOPIC PREGNANCY

Very few  clinical  conditions  exhibit  so  varied  features like that of disturbed tubal pregnancy. The clinical types are correlated with the morbid pathological changes in the tube subsequent to implantation and the amount of intraperitoneal bleeding. However, clinically three distinct types are described:
■  Acute (tubal rupture or abortion) Unruptured
■   Subacute (chronic or old)

I ACUTE ECTOPIC PREGNANCY

An acute ectopic is fortunately less common (about 30%) and it is associated with cases of tubal rupture or tubal abortion with massive intraperitoneal hemorrhage.
Patient profile: (1) The incidence is maximum between the age of 20 and 30 years, being the maximum period of fertility. (2) The prevalence is mostly limited to nulliparity or following long period of infertility.
Mode  of onset:  The  onset is  acute.  The patients, however, have got persistent unilateral uneasiness in about  one-third of  cases before the acute symptoms appear.

Symptoms: The classic triad of symptoms of  dis­ turbed tubal pregnancy are: abdominal pain (100%), preceded by amenorrhea (75%) and lastly, appearance of vaginal bleeding (70%).
■    Abdominal  pain  (100%)  is   the  most  constant feature. It is  acute,  agonizing  or  colicky.  Otherwise it  may be a vague soreness. Pain is located at lower abdomen: unilateral, bilateral or may be generalized. Shoulder  tip  pain  (25%)  (referred  pain  due  to diaphragmatic irritation from hemoperitoneum) may be present.
■    Vaginal bleeding (70%) may be slight and continuous. Expulsion   of   decidual   cast   (5%)   may   be   there (Fig. 16.3).
■    Amenorrhea:  Short period of 6-8  weeks  (usually); there may be delayed period or  history  of vaginal spotting. Amenorrhea may be absent even.
■   Syncope (10%): Dizziness, high headedness may be an initial presentation. It is often due to intra-abdominal bleeding  following  rupture  of  a  tubal  ectopic pregnancy.

SIGNS
■   General  look  (diagnostic):  The  patient  lies  quiet and conscious, perspires and looks blanched (due to hemoperitoneum).
■   Pallor:  Severe and proportionate to the amount of internal hemorrhage.
■   Features of shock: Pulse-rapid and feeble, hypo­ tension, extremities-cold clammy.
■   Abdominal examination: Abdomen  (lower  abdo­ men)-tense, tumid, tender. No mass is usually felt, shifting dullness present, bowels may be distended. Muscle guard-usually absent.
■    Pelvic   examination  is   less   informative   due   to extreme  tenderness  and  it  may  precipitate  more intraperitoneal hemorrhage due to manipulation. The findings  are:  (i)  Vaginal  mucosa-blanched  white. (ii) Uterus seems normal in size or slightly bulky and soft. (iii) Extreme tenderness on fornix palpation or on movement of the cervix. Cervical motion tenderness (75%). (iv) No mass is usually felt through the fornix. (v) The uterus floats as if in water. Caution: Vaginal examination may precipitate more hemorrhage due to manipulation.
I UN RUPTURED TUBAL ECTOPIC PREGNANCY

High  degree  of  suspicion  and  an  ectopic  conscious clinician can only diagnose the entity at its prerupture state.  There is a high frequency of misdiagnosis and physician delay. The physician should include ectopic pregnancy in the differential diagnosis when a sexually active female has abnormal vaginal bleeding and/ or abdominal pain. This is especially so when the woman has got some risk factors.


Symptoms:  •  Presence of delayed period or spotting with  features  suggestive  of  pregnancy.   +  Uneasiness on one side of the flank which is continuous or at times colicky in nature.
Signs: Bimanual examination-(i) Uterus is usually soft showing evidence of early pregnancy. (ii) A pulsatile small, well-circumscribed tender mass may be felt through one fornix separated from the uterus. The palpation should be gentle, else rupture may precipitate and massive intraperitoneal hemorrhage when shock and collapse may occur dramatically.
Investigations (Figs. 16.9A to D): With the advent of Transvaginal Sonography (TVS), highly sensitive radio­ immunoassay of 13-hCG and laparoscopy, more and more ectopics are now diagnosed in unruptured state (details of diagnosis see below). Management: P. 175.
SUBACUTE (CHRONIC) ECTOPIC: It is indeed dificult at times to diagnose old ectopics because of variations of clinical  features  mentioned  earlier.  Onset:  The  onset is insidious. The patient had previous attacks of acute pain from which she had recovered or she had chronic features from the beginning. The confusing features are: (1) Absence ofamenorrhea. (2) Irregular vaginal bleeding. (3)  Lower  abdominal  pain.   ( 4)  Apparently  normal general condition. (5) Presence of pelvic mass on internal examination. (6) Previous history of tubectomy operation or IUD insertion.

Symptoms:
11    Amenorrhea: Short period of 6-8 weeks is usually present.
11    Lower abdominal pain is present. It starts as an acute one and gradually becomes dull or colicky in nature.
11   Vaginal bleeding appears sooner or later following the pain. Expulsion  of  decidual  cast  may  be  present  (Fig.  16.3).



Complete absorption (rare) 1. Tubal mole -{
Abortion ---  Pelvic hematocele

Chapter 16: Hemorrhage in Early Pregnancy     ll

On examination (signs):
!I   The patient looks ill, hemodynamically stable. El    Pallor varying degree is present.
11    Pulse: Persistently high-a conspicuous finding.
11   Abdominal examination: (i) Tenderness and muscle guard on the lower abdomen especially on the affected side are a striking feature. (ii) A mass in the lower abdomen may be felt.
a   Bimanual examination is painful and reveals: An ill-defined, boggy  and  extremely  tender  mass  is  felt  through  the posterolateral fornix extending to the pouch of Douglas. The mass may push the uterus to the opposite side.
11   The trophoblast cells are dying or dead. Serum  -hCB is low, static or even negative.
11    USG: Heterogenous  pelvic  mass with separate normal  uterus is   seen.   Uterine   cavity   is   empty.   Laparoscopy  is   helpful to  the diagnosis and therapy as well. Management: Unilateral
salpingectomy and removal of blood clots are done.

I DIAGNOSIS OF ECTOPIC PREGNANCY
ACUTE ECTOPIC: The classic history of acute abdominal pain with syncopal attack and associated with features of  intra-abdominal  hemorrhage  in  a  woman  of childbearing age points to a certain diagnosis of acute ectopic. No time should be wasted for investigations other than estimation of hemoglobin and blood grouping (ABO and Rh).
Differential  diagnoses  of acute ectopic pregnancy are: (1) Acute appendicitis, (2) ruptured corpus luteum. Clinical presentation is similar to ruptured tubal ectopic pregnancy­ pregnancy test is negative, (3) twisted ovarian tumor, ( 4) ruptured chocolate cyst.
Investigations  for  the  diagnosis  of  tubal  ectopic pregnancy:
ci    Blood examination should be done as a routine for: (i)   Hemoglobin.   (ii)   Hematocrit.   (iii)   ABO   and Rh grouping. (iv) Total white cell count and differential


Tubal abortion
beginning



-	Complete---+  Pelvic hematocele 2. Tubal abortion	[
Incomplete-+ Diffuse intra.peritoneal hemorrhage


Complete
abortion (rare)




-	Roof ---	--+  Diffuse intra.peritoneal hemorrhage (p. 178) 3. Tubal rupture     [


Complete abortion

Floor----  lntraligamentary hematoma


Roof 4. Tubal perforation {


Secondary abdominal pregnancy (rare) (p. 178)
Tubal mole

Floor-----+  Secondary intraligamentary pregnancy (rare)

5. Continuation of pregnancy-rarest

Figs.  16.9A to  D:  Modes  of  termination  of  tubal  pregnancy.
r
ID Chapter 16: Hemorrhage in Early Pregnancy
count. (v) Erythrocyte Sedimentation Rate (ESR). There may be varying degrees of leukocytosis and raised ESR.
a  Estimation of P-hCG: Urine pregnancy test-ELISA is sensitive to 10-50 mIU/mL and is positive in 95% of ectopic pregnancies. A single estimation of P-hCG level  either  in  the  serum  or  in  urine  confirms pregnancy but cannot determine its location. The suspicious findings are:  (I)  Lower concentration of P-hCG compared to normal intrauterine pregnancy, (2) Doubling time in plasma fails to occur in 2 days.
11    Sonography:  Transvaginal  Sonography  (TVS)  is more informative. The diagnostic features are: (1) Absence of intrauterine pregnancy with a positive pregnancy test.  (2)  Fluid  (echogenic)  in  the  pouch of Douglas. (3)Adnexal  mass  clearly  separated  from the ovary. ( 4) Rarely cardiac motion may be seen in an unruptured tubal ectopic pregnancy. Color Doppler Sonography:  (TV-CDS)-can  identify  the  placental shape (ring-of-fire pattern) and enhanced blood flow pattern outside the uterine cavity.
El    Combination   of   quantitative    -hCG   values and  sonography: TVS provides visualization of a wellformed intrauterine gestational sac as early as 4-5 weeks  from  the  last  menstrual  period.  The  lowest level of serum  P-hCG at  which a gestational sac  is consistently visible using TVS (discriminatory zone) is ".l,500 IU/L. The corresponding value of serum P-hCG for TAS is 6,000 IU/L.  (1)  When the   -hCG value is greater than 1,500 IU/L and there is an empty uterine cavity, ectopic pregnancy is more likely. (2) Failure to double the value of  -hCG by 48 hours along with an empty uterus is very much suggestive.
11     Laparoscopy  (Figs. 16.10, 16.12 and 16.13) offers benefit  in  cases  of  confusion  with  other  pelvic

















Fig. 16.10: Laparoscopic view of an unruptured tubal ectopic pregnancy (right). Hugely dilated ampulla is seen (arrow).







lesions. It should be employed only when the patient is  hemodynamically  stable.  Advantages  are:  (i) Confirmation of diagnosis. (ii) Removal of the ectopic mass using operative procedures at the same time. (iii) Direct injection of chemotherapeutic agents into the ectopic mass-when medical management is decided. However, laparoscopy runs the risk of false-positive or false-negative diagnosis in 2-5% of cases.
:1    Culdocentesis is simple and safe. Where sensitive TVS or laparoscopy is not readily available, culdocentesis is still a diagnostic alternative. Unfortunately negative culdocentesis does not rule out an ectopic pregnancy neither a positive result is very specific. Through an 18-gauge lumbar puncture needle fitted with a syringe, the posterior fornix is punctured to gain access to the pouch of Douglas. Aspiration of nonclotting blood with hematocrit greater than 15% signifies ruptured ectopic pregnancy.
Dilatation and curettage: Identification of decidua without  villi  structure  is  very  much  suggestive. Chorionic villi that float in normal saline as lacy fronds are diagnostic of intrauterine pregnancy.
11     Serum progesterone: Level greater than 25 ng/mL is suggestive of viable intrauterine pregnancy whereas level less than 5 ng/mL suggests an ectopic or abnormal intrauterine pregnancy. It is not commonly done.
11    Laparotomy offers benefit when in doubt. The old axiom, 'open and see'  holds good  especially when the patient is hemodynamically unstable. One should not be ashamed of having a negative laparotomy or laparoscopy, rather to be disgraced for the mistake in diagnosis with the eventual fatality.
Differential diagnosis of subacute ectopic pregnancy:
Differential diagnosis of ectopic pregnancy: Clinical scenarios that mimic ectopics are:  0 Incomplete abortion, 0  salpingitis, 0  appendicitis, (D  ruptured chocolate cysts and O ruptured corpus luteum. The main diagnotic features for ectopic pregnancy are: 0 Positive test for pregnancy (hCG) in urine or serum; 0, USG: presence of gestation sac in the adnexae and uterine cavity is empty.

MANAGEMENT OF ECTOPIC PREGNANCY

Over  the  past  decade,  the  management  of  ectopic pregnancy (in uncommon locations) has evolved from a radical operative approach (salpingectomy) to a more conservative surgical or medical treatment. This has been possible due to early diagnosis, advanced laparoscopic techniques  and  ability  to  monitor  the  patient  after conservative surgical or medical treatment. However, the type of treatment must be individualized and depends more on clinical presentation (Flowchart 16.3).
Chapter 16: Hemorrhage in Early Pregnancy     -·
Flowchart  16.3:   Scheme  of management  of tubal  ectopic  pregnancy.

■ Detailed history, evaluation of high-risk factors and examination ■ Urine-/3-hCG (ELISA)/serum /3-hCG
■ Ultrasound scan (transvaginal preferred)

Be ectopic minded
I
l	l	l
• Some clinical features	• Some clinical features	• /3-hCG-positive
• /3-hCG-negative	• /3-hCG-positive	• Strong clinical features
l
l
l
• Patient in shock/unstable
hemodynamically
l
l
l
Repeat /3-hCG in 1 week	USS (TVS)

Negative	(Discriminatory zone lof//3-hCG	Resuscitation and laparotomy
on TVS= 1500 m U mL)
j

Pregnancy excluded	Ruptured tubal ectopic pregnancy

l	Salpingectomy
Intrauterine	Empty uterine cavity
sac	with adnexal mass
l
l


Determine viability	Laparoscopy
• /3-hCG increase >60% in 48 hours • Serum progesterone >25 ng/ml
• Repeat USG	Unruptured tubal Intrauterine                                                          ectopic pregnancy
j.
pregnancy
l	I
Expectant	Medical	Surgery
l
■ Initial /3-hCG <1000 IU/L	Laparoscopy/ ■ Falling hCG titer
laparotomy
■ Ectopic mass diameter is <4 cm
Direct local
Systemic
■ MTX (50 mg
No evidence of
■ bleeding or rupture	(laparoscopy/	■ Actinomycin /m2,  IM)
USS guided)
on TVS
■ No cardiac activity	i
■ MTX
■ Potassium chloride	Conservative	Extirpative
l
l

Salpingectomy

J
Expressing out	Salpin­	Salpingo­	Segmental
from distal tube	gostomy	tomy	resection
l
l
l
l

I	/3-hCG follow-up to detect persistent trophoblastic disease (ectopic pregnancy)	I (USS: Ultrasound Scan; TVS: Transvaginal Sonography; MTX: Methotrexate)


ACUTE
Principle: The principle in the management of acute ectopic  is  resuscitation  and  laparotomy  and  not resuscitation followed by laparotomy.


Antishoclc  treatment:  Antishock  measures  are  to be taken with simultaneous preparation for urgent laparotomy.
•   Ringer's solution (crystalloid) is started, if necessary with venesection.
&I Chapter 16: Hemorrhage in Early Pregnancy
Indications are: (i) Initial serum hCG level less than 1,500  IU/L  and  the subsequent levels  are falling.  (ii) Gestation sac size less than 4 cm. (iii) No fetal heart beat on TVS. (v) No evidence of bleeding or rupture on TVS.
Conservative management may be either medical or surgical. Otherwise salpingectomy is done.
The  advantages  of conservative  management  are: (1) Significant reduction in operative morbidity, hospital stay as well as cost. (2) Improved chance of subsequent intrauterine pregnancy and (3) Less risk of recurrence.



Fig.  16.11: Salpingectomy. Note the placement of the clamps.

•   Arrangement is made for blood transfusion. Even if availability of blood is delayed, Iaparotomy is to be done desperately.
•   After drawing the blood  samples for  grouping  and cross matching, volume replacement with crystalloids is to be done.
Laparotomy:  Indications  of  laparotomy  are-(i) Patient hemodynamically unstable.  (ii)  Laparoscopy contraindicated. (iii) Evidence of rupture. The principle in Iaparotomy is 'quick in quick out'.
Steps:
♦   Abdomen is opened  by infraumbilical longitudinal incision.
♦  To grasp the uterus and draw it up undervision.
♦  The tubes and ovaries of both the sides are quickly inspected to find out the side of rupture.
♦   Salpingectomy (Fig. 16.11) is the definitive surgery. The excised tube should be sent for histological examination.
♦   The  ipsilateral ovary  and  its  vascular  supply  is preserved.
♦   Subtotal   hysterectomy   is   not   needed   unless   it is  an interstitial pregnancy.
Its routine use is not advocated because of its adverse reaction.
In case, where donated blood is not available, the fresh blood from the peritoneal cavity may be collected for autotransfusion. The collection is done through strainer consisting of 4-5 layers of sterile gauze pieces into a bottle containing citrate solution (3.8%) in the proportion of five parts of blood to one part of citrate solution.
Resumption of ovulation and contraception: About 15% of women ovulate by 19 days and about 25% ovulate by  the 30th postoperative day.  Contraception should ideally be commenced at the time of hospital discharge.

MANAGEMENTOFUNRUPTUREDTUBAL PREGNANCY

■   Expectant	■  Medical	■   Surgical ■   Conservative	■   Ablative
Expectant management: Where only observation is done hoping spontaneous resolution.

Medical management: Number of chemotherapeutic agents have been used either  systemic or direct local ( under sonographic or laparoscopic guidance) as medical management of ectopic pregnancy. The drugs commonly used for salpingocentesis are: methotrexate, potassium
chloride, prostaglandin (PGF2a,), hyperosmolar glucose or actinomycin.

Criteria for medical therapy: The patient must be-0 Asymptomatic and compliant. 8 Hemodynamical­ ly stable. I) Serum hCG level less than 3,000 IU/L. 0 Tubal diameter less than 4 cm without any fetal cardiac activity. 9 There is no intra-abdominal hemorrhage. For systemic therapy, a single dose of methotrexate (MTX) 50 mg/m2 is commonly given intramuscularly.

Methotrexate (MTX) is a folic acid antagonist. It blocks dihydrofolate  reductase  and  prevents  conversion  of dihydrofolate to tetrahydrofolate which is the active form of folic acid. There is block in the synthesis of DNA, RNA and protein.
Monitoring is done by measuring serum  P-hCG on
D4 and Dr When the decline in hCG between D4 and D7 is ?.15%, patient is followed up weekly with serum hCG
until hCG less than 10 mlU/mL. If the decline is less than
15%, a second dose of MTX 50 mg/m2  is given on Dr
Multidose regimen is used for advanced cases gestations or those with embryonic cardiac activity. These women may have more side effects. Multidose Methotrexate
(MTX)  includes:  MTX-1 mg/kg  IM  on  D1,3,5,7   and
leucovorin-0.1 mg/kg IM on D2 4 6 8•   Serum  P-hCG is
monitored weekly until less than 5.0  IU/mL. Commonly outpatient monitoring is preferred in unless more safety is needed.
Side effects are more common with multiple doses. Most common side effect is flatulence. Others are: mucositis, gastroenteritis,  hepatitis,  anemia  and  bone  marrow depression. Patient may complain  of  pain  following therapy. This is due to death of the trophoblast cells and separation of  ectopic  pregnancy from  the tubal wall. Generally it subsides of its own.
Monitoring of therapy: Multidose MTX:  Failure to decline in the levels of serum P-hCG ?.15% between D
4
and  D7,   following  a  single dose therapy,  patient  needs
multidose  MTX  therapy.  Overall  success  rate  of  MTX
Chapter 16: Hemorrhage in Early Pregnancy    &I






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Figs. 16.12A to C: Laparoscopic linear salpingostomy for unruptured tubal pregnancy: (A) Linear incision on the antimesenteric border; (Bl Gestation sac is removed; (C) Incision margins left unsutured.


therapy is 90%. Patient should be monitored with serum P hCG  levels  similar  as  in  medical  therapy  (discussed above).
CONTRAINDICATION OF METHOTREXATE THERAPY Absolute contraindications:
■   Breastfeeding.	■  Hepatic, renal or hemato-■   Significant anemia.                  logic dysfunction.
■   Immunodeficiency state.  Relative contraindications: ■   Sensitivity to methotrexate. ■   Embryonic cardiac motion. ■   Active pulmonary disease. ■   Gestational sac >3.5 cm.

Conservative  surgery:  The  procedure   is   done laparoscopically. Surgery is the most definitive method of treatment.
Indications:  (a)  Cases  not fulfilling the criteria  of medical therapy. (b) Cases where P-hCG levels plateus or rises    despite    medical    therapy.    (c)    Tubal    rupture (d) Persistent fetal cardiac activity.
TYPES OF SURGERY:
1.  Linear salpingostomy: A longitudinal incision is made on the antimesenteric border directly over the site of ectopic pregnancy.   After   removing   the   products   (by   suction), the  incision  line  is kept open to be healed  later  on by secondary intention. Hemostasis is achieved by needle point electrocautery or laser (Figs. 16,12A to C).
2.  Segmental resection: This is of choice in isthmic pregnancy. End-to-end anastomosis can be done immediately or at a later date after appropriate counseling of the patient.
3.  Fimbrial expression: This is ideal in cases of distal ampullary (fimbrial) pregnancy and is safe.
4.  Salpingectomy: It is done when-(i) whole of the affected tube is damaged, (ii) contralateral tube is normal or (iii) future fertility is not desired.


Following conservative surgery or medical treatment, estimation of P-hCG should be done weekly till the value becomes less than 5.0 mlU/mL. Additional monitoring by TVS is preferred. Following laparoscopic salpingostomy, persistent ectopic pregnancy ranges between 4 and 20%.
Persistent ectopic  pregnancy  (10-15%) is due  to incomplete removal of trophoblast. It is high after fimbrial expression and in cases where initial serum P-hCG level is greater than 3,000 IU/L. Prophylactic single dose MTX (1 mg/kg) IM is effective to resolve the problem.
Rh-NEGATIVE WOMEN: In Rh-negative women not yet sensitized  to  Rh antigen,  anti-D  gammaglobulin-50 µg (if gestation <12 weeks) or  300 mg  (if  >12 weeks) intramuscularly is administered soon following operation to prevent isoimmunization.
PROGNOSIS  OF   TUBAL  PREGNANCY:  Immediate prognosis so far as maternal mortality is concerned has been markedly reduced (0.05%) due to early diagnosis, adequate  blood  replacement  and  surgery  even  in desperately ill patient. Chance of recurrence of ectopic is 1 in 10. In a woman without any histo1y of subfertility due to tubal pathology, fertility is not affected adversely. Expectant or medical management gives better result compared to salpingectomy (Figs. 16.13A to C).
PREVENTION OF RECURRENCE OF TUBAL PREGNANCY: Incidence of subsequent Intrauterine Pregnancy (IUP) is  60-70%,  in  women  with  unruptured  tubal  ectopic pregnancy treated by conservative surgery.
The incidence of subsequent ectopic pregnancy is about 10-20% and successful conception is about 60%.
Salpingostomy done  for  unruptured  tubal  ectopic pregnancy does not increase the risk of ectopic pregnancy
ZI Chapter 16: Hemorrhage in Early Pregnancy











Figs. 16.13A to C: Tubal twin pregnancy: (A) Bulging at the two sites of the tube; (B) USG-two gestational sacs with fetal poles; (C) Doppler study to show cardiac motion (Courtesy: Dr A Halder and Dr J Khamaroo).


compared to salpingectomy.  Conservative surgery for unruptured tubal ectopic pregnancy is beneficial.
Future advice: Main concern is the risk of recurrence. Whenever there is amenorrhea, pregnancy test is done and if positive, high resolution TVS is done to know the site of pregnancy.
UNCOMMON  ECTOPIC  PREGNANCIES:  Read  more Dutta's Clinics in Obstetrics, Ch. 17, 18, 19, 20.

INTERSTITIAL PREGNANCY (FIGS. 16.14A TO C)

It is the rarest variety of  tubal  pregnancy.  Because of the thick  and  vascular  musculature  of  the  uterine  wall  with greater distensibility, the fetus grows dissecting the muscle fibers for a longer period (12-14 weeks) before termination occurs. The usual termination is rupture. It is associated with massive intraperitoneal hemorrhage due to its combined vascularization by the uterine and ovarian arteries. On rare occasion, abortion occurs through the uterine cavity.
The diagnosis before rupture is very difficult. Asymmetrical enlargement of the uterus especially detected during active contraction, is a conspicuous finding.
USG diagnostic criteria are: (a) Uterine cavity empty, (b) Gestation sac is located laterally in the intramural part of the tube, (c) GS is surrounded bya thin layer(<5 mm) ofmyometrial mantle, and (d) Presence of "interstitial line sign''. It is a thin  echogenic line extending from the central uterine cavity echo   up to the interstitial sac. 3D-USG or MRI (non-contrast) is also helpful for localization of uncommon ectopic like cervical,  ovarian, cesarean


scar, intestinal or abdominal. Laparoscopy is  diagnostic and therapeutic at the same time.
Surgical management is by either laparoscopy or laparotomy: Management options: (a) Expectant management: When
Serum  -hCG level is low or falling, (b) Medical management: Patient hemodynamically stable, methotrexate is used either systemic or local, (c) Surgical management: Cornuostomy/ cornual resection (laparoscopy is preferred over hysteroscopic resection). Hysterectomy is rarely needed.

ABDOMINAL  PREGNANCY

PRIMARY:  Primary  implantation  of  the  fertilized  ovum  on the peritoneum is so rare that its existence is questionable. However, the criteria laid down by Studdiford to diagnose primary   abdominal   pregnancy   are:   (1)   Both  the  tubes and  ovaries  are  normal  without  evidence  of  recent  injmy. (2) Absence of uteroperitoneal fistula. (3) Presence of a pregnancy related exclusively to the peritoneal surface and young enough to eliminate the possibility of secondary implantation following primary nidation in the tube.
SECONDARY: Abdominal pregnancy is almost always secondaty, the primaty sites  being tube,  ovary or  even the  uterus-the conceptus escapes out through the rent in the uterine scar. The average incidence is about 1 in 3,000 pregnancies. With the use of ART incidence is found rising.
Symptoms:  (1) History suggestive of disturbed tubal pregnancy during early months (pain lower abdomen and vaginal bleeding) is often present. (2) Minor ailments of normal uterine














Figs. 16.14A to C:  (A)  Interstitial pregnancy;  (B)  Ruptured interstitial pregnancy-subtotal hysterectomy done; (C)  Laparoscopic view of unruptured interstitial pregnancy (see arrow).
Chapter 16: Hemorrhage in Early Pregnancy    Im' ..

pregnancy are often exaggerated such as nausea,  vomiting, constipation, pain abdomen and increased fetal movements.
Signs in advanced pregnancy: (1) Uterine contour is not well-defined even by massaging the abdominal wall, as the Braxton-Hicks contraction is absent in abdominal pregnancy. (2) Fetal parts are felt easily and persistent abnormal attitude and position of the fetus on repeated examination is quite common. While abnormal high position of the fetus is commonly found in intraperitoneal pregnancy, the fetus is lying low in intraligamentary pregnancy.
Internal examination: The uterus is difficult to separate from the abdominal mass. Uterus it is enlarged (12-16 weeks) but the cervix is not typically soft and is usually displaced depending upon the position of the sac.

Imaging Studies
USG Diagnostic Criteria (Early pregnancy): 1.  Uterine cavity empty.
2.  Absence of any dilated tube and/or any complex adnexal mass.
3.  The gestational sac is surrounded by loops of bowel and is separated from them by peritoneum.
4.  Oligohydramnios is common.
5.  Fluctuation of the sac seen, with pressure of the TV probe towards the posterior cul-de-sac.
6.  MRI is helpful to confirm the diagnosis, localize the placenta over any vital structures (major blood vessels).
7.  USG/MRI is used to plan the surgety.
Magnetic resonance imaging (MRI) can confirm the diagnosis and may be very accurate. Computed tomography is diagnostic and is superior to MRI. CT has the risk of radiation.
Diagnosis: Its rarity, variegated clinical pictures and not keeping in mind the possibility lead to confusion in diagnosis. A high index of suspicion, elevated serum beta hCG and USG/ MRI findings are helpful to diagnosis.
Highly suggestive features for late cases: (1) Repeated failure of induction for intrauterine fetal death. (2) During induction of labor by oxytocin, uterine contraction could not be excited. Surest evidence is on laparotomy.
Management: (a) Early pregnancy-Laparoscopic removal is done. Systemic methotrexate with USG-guided feticide may be done.  {b) In advanced pregnancy: Urgent laparotomy irrespective of period of gestation. The risks of continuation of pregnancy are: (1) Catastrophic hemorrhage. (2) Fetal death. (3) Increased fetal malformation. (4) Increased neonatal loss (50%). Thus, continuation of pregnancy for few weeks hoping the baby to become mature enough to survive can only be justified in exceptional circumstances. The patient and her relatives should be explained about the eventuality. During the period, the patient should be in the hospital.
Laparotomy:The ideal surgery is to remove the entire sacfetus, the placenta and the membranes. This may be achieved if  the placenta is attached to a removable organ like uterus or broad ligament. If the placenta is attached to vital organs, it is better to take out the fetus and leave behind the placenta and the sac, after tying and cutting the cord flushed with the placenta. In such a situation, placental activity is to be monitored by quantitative serum P-hCG level and ultrasound. Complete absorption of the left behind placenta occurs through aseptic autolysis. Methotrexate has been used as an adjunct therapy to surgery.

Complications  include secondary hemorrhage, intestinal obstruction and infection.
Prognosis: Because of the risk mentioned before maternal mortality is less than 5% but morbidity is high. Perinatal mortality approximates 90%. Fetal malformation could be as high as 50%. Normal infants have been reported in 10% of cases.

OVARIAN PREGNANCY

Spiegelberg's criteria in diagnosis of ovarian pregnancy  are­ (1) Tube on the affected side must be intact. (2) The  gestation sac must be in the position of the ovary. (3) The  gestation sac is connected to the uterus by the ovarian ligament. ( 4) The ovarian tissue must be found on its wall on histological  examination.
USG diagnostic criteria: (a) Uterine cavity: empty, {b) Wide echogenic ring with an  internal anechoic area on  the ovary, (c) Gestation sac (GS)/embryo may be seen, {d) Negative "sliding organ sign" (GS cannot be separated from the ovary on gentle probe pressure), (e) Corpus luteum could be seen separate from the ovary.

Treatment Options: Surgical
a.  Laparoscopic method of removal of conceptus, enucleation or wedge resection is the preferred method.
b.  Oophorectomy is done-when there is (i) excessive bleeding or {ii) coexisting ovarian pathology.
Medical: Systemic methotrexate can be used when: ( a) Risk of surgery is high, {b) Postoperatively, when there is persistent GTN. In advanced pregnancy, rupture is an inevitable phenomenon and salpingo-oophorectomy is the definite surgery.

CORNUALPREGNANCY
Pregnancy  occurring  in  rudimentary  horn  of   !]	!]
 
a  bicornuate uterus is called cornual pregnancy   ,:·	­ (Fig. 16.15).  The  overall  prevalence  is  1  in   'K     · .   76,000  pregnancies.  The  horn  does  not  usually communicate   with  the   uterine  cavity.   The impregnation is presumed to occur by a spermatozoa which passes through the normal half of the-uterus and tube. It then fertilizes an ovum either in the peritoneal cavity or  in the tube connected to the rudimentaty horn by trans peritoneal migration. The concerned ovum is usually shed from the ovary on the same side of the rudimentary horn.
 
!]
 
The general and local reactions are similar to those in the tubal pregnancy. But these are intensified and pregnancy may continue for longer time. Termination by rupture is inevitable between 12 and 20 weeks with massive intraperitoneal hemorrhage.
USG diagnostic criteria: ( a) Visualization of a single interstitial portion of the tube in the main uterine body, {b) GS is seen mobile and is separate from the uterus, (c) GS/product of conception is surrounded by myometrium, {d) Presence of a vascular pedicle connecting the GS to the unicornuate uterus.
The diagnosis is seldom done before the catastrophe. The condition is commonly diagnosed as fibroid or ovarian tumor with pregnancy. Even on laparotomy, the exact position is confused with interstitial pregnancy. Position of the round ligament which is attached to the sac and the long pedicle by which it is attached to the uterus are the diagnostic points.  Surgery  includes  removal  of the  rudimentary  horn
mJ Chapter 16: Hemorrhage in Early Pregnancy
the fundus. (b) Uterine bleeding following amenorrhea, without cramping pain (90%). (c) Products of conception entirely confined within and firmly attached to endocervix. (d) A closed internal cervical os and a partially opened external os (Figs. 16.16A to C). Confirmation is done by histological evidence of the presence of villi inside the cervical stroma.
Management:
■  Medical  management:  Systemic  methotrexate,  local injection with KC!. 11 Surgical management: When bleeding is lifethreatening
Surgical procedures used are: •   Dilatation and curettage. With or without adjunctive methods: • Uterine artery ligation.
•   Uterine Artery Embolization (EUA) Other procedures of management:


Fig. 16.15: Cornual pregnancy.

by laparoscopy/laparotomy. If the pedicle is short and the attachment is wide, hysterectomy may have to be done (Fig.16.15).

CERVICAL  PREGNANCY
This is a rare (1 in 16,000 pregnancies) variant of ectopic pregnancy when the implantation occurs in the cervical canal at or below the internal os. Erosion of the walls by the trophoblasts occurs resulting in thinning and distension of the canal. The condition is commonly confused with cervical abortion. In cervical pregnancy, the bleeding is painless and the uterine body lies above the distended cervix. Intractable bleeding following evacuation or expulsion of the products brings about suspicion. The morbidity and mortality is high because of profuse hemorrhage (Figs. 16. 16A to C).
USG Diagnostic Criteria
(a)  Uterine cavity-empty.  (b)  Cervix-barrel shaped. (c) GS: located below the internal OS. (d) Absence of 'sliding sign' (in a case with miscarriage, when probe pressure is applied  on the cervix, the gestational sac slides against the cervical canal whereas in cervical pregnancy and scar ectopic pregnancy, it  does  not happen so).  (e) Increased  blood  flow  around the GS  is seen while using color Doppler.
Clinical diagnostic criteria (Rubin-1983) for cervical pregnancy are-(a) Soft, enlarged cervix equal to or larger than

•   Intracervical vasopressin injection.
•   Hemostatic cervical sutures on the lateral aspects of the cervix (3 and 9 o'clock position).
•   Folley  balloon  catheter  to  tamponade  bleeding  after  the curettage.
•   Hysteroscopic resection with UAE •   Hysterectomy.
Criteria for successful conservative management •   Pregnancy <12 weeks.
•   Absence of fetal cardiac activity. •   Low serum beta hCG levels.

PREGNANCY OF UNKNOWN LOCATION

No sign of either intra- or extrauterine pregnancy or retained products of conception antransvaginal ultrasound in a woman with a positive pregnancy test.

CESAREAN SCAR PREGNANCY

Cesarean  scar pregnancy is defined as  implan­ tation  into  the  myometrial  defect  in  the  site  of the  previous  uterine  scar (for cesarean delivery). Overall prevalence is  1 in 2500-3000 pregnancies. Outcome: (a) may continue viable pregnancy, or (b) may end in miscarriage within the scar.















Figs. 16.16A to C: Cervical pregnancy-hysterectomy done  (showing  Rubin's  diagnostic  criteria):  (A) Globular  cervix  with partially opened external os; (B) Uterus cut opened through the anterior wall to show the huge hemorrhagic mass occupying the cervical canal with empty uterine cavity; (C) When the mass was dissected, the cervical wall showed macroscopic evidence of invasion of trophoblastic tissue (confirmed on histology).
Chapter 16: Hemorrhage in Early Pregnancy    JI

USG diagnostic criteria (Figs. 16.17A and B) (Combined TAS and TVS): (a) Empty uterine cavity, (b) GS or solid mass of trophoblast cells located anteriorly at the level of internal OS and embedded at the niche scar, (c) Thin or absent layer of myometrium, (d) Distinct vascular flow on Doppler study, (e) Closed endocervical canal, (f) Yolk sac, embryo, cardiac activity may be seen, (g) Negative 'slide organs' sign.
Diagnostic features of cesarean scar pregnancy on MRI are similar to that of USG. MRI is needed when the USG diagnosis is inconclusive. Serum beta hCG level may be useful for management formulation.
Types: (a) Type 1 (endogenic)-growing towards the uterine cavity, (b) Type 2 (exogenic)-growing outwards. Risk of rupture and hemorrhage is high in exogenic type.
Treatment options: (a)  Associated with high maternal morbidity and mortality, (b) Surgical rather than medical method is found most effective, (c) Live birth following management has been reported (though rare), (d) Medical treatment: Methotrexate














Figs.  16.17A and B: (A) Ultrasonographic view of cesarean scar pregnancy. Layer of myometrium is absent over the implantation site  (see arrow);  (B)  Cesarean  scar  pregnancy  (exogenic  type), causing rupture and hemorrhage (see arrow).

is administered by systemic (IM) or local injection into the gestation sac. (e) Surgical treatment: Evacuation (S/E) or excision of pregnancy by: Open or laparoscopic or hysteroscopic method. Additional hemostatic measures used are: Foley catheter insertion or UAE or uterine artery ligation or hysterectomy (in advanced cases).

HETEROTOPIC PREGNANCY

Intrauterine pregnancy may be co-existent with tubal or rarely with cervical or ovarian pregnancy. Diagnosis is difficult. Incidence   is about 1 in 8,000 pregnancies at present. It is more common following ART procedures.
USG Diagnostic Criteria
A.  Demonstration of an intrauterine pregnancy and a co-existing ectopic pregnancy,
B.  A higher than expected level of serum beta hCG in relation to gestational age.
C. There may be persistently  raised level of serum beta hCG even following miscarriage or termination of pregnancy.
Management options: The intrauterine pregnancy should be considered in the management plan.

Medical Management
A.  Methotrexate can be given in a case where: (i) Intrauterine pregnancy is nonviable, (ii) Patient does not wish to continue the pregnancy.
B.  Local  injection of potassium chloride  or  hyperosmolar glucose with aspiration of the sac contents may be done (feticide)-(i) Surgery: Removal of ectopic pregnancy, if the patient is hemodynamically unstable following simultaneous resuscitation. (ii) Expectant management: When heterotopic pregnancy is nonviable.
Rhesus D (Rh D) negative women with ectopic preg­ nancy should be given anti-D immunoglobulin .



•

►   Ectopic Pregnancy
►   An ectopic pregnancy is one in which the blastocyst is implanted and develops outside the normal endometrial cavity. ►  The different sites of ectopic pregnancy are: tubal (most common), ovarian, abdominal, cervical and others.
►  The common causes of ectopic pregnancy are: salpingitis, PIO, contraception failure (IUCD), tubal ligation, ART procedures and tubal surgery.
►  Other uncommon sites of ectopic pregnancy are: (a) abdominal pregnancy, (b) ovarian pregnancy, (c) cornual pregnancy, (d) cervical pregnancy, and (e) cesarean scar pregnancy.
►  Presentation of a women with ectopic pregnancy includes: abdominal pain, amenorrhea and vaginal bleeding.
►   Diagnosis of ectopic pregnancy is made by: positive hCG (either in urine or serum), transvaginal sonography (no intrauterine pregnancy, fluid in the pouch of Douglas and adnexal mass) and laparoscopy/laparotomy is done for confirmation.
►   Treatment of ecotopic pregnancy could be surgical or medical. Surgery could be done either by laparoscopy (common) or by laparotomy. Either salpingotomy or salpingectomy is done.
►  Ruptured tubal ectopic pregnancy should be managed by simultaneous resuscitation and laparotomy and it is not resuscitation followed by laparotomy.
►  Unruptured tubal ectopic pregnancy could be treated medically with methotrexate once the criteria are fulfilled.
►   Prospect of fertility following an ectopic pregnancy: fertility is not adversely affected for a woman without any history of subfertility. Expectant or medical management often gives improved result compared to salpingectomy.
•·Im Chapter 16: Hemorrhage in Early Pregnancy
GESTATIONAL TROPHOBLASTIC DISEASES (GTD)
DEFINITION:  Gestational Trophoblastic Disease (GTD) encompasses a spectrum of proliferative abnormalities of trophoblasts associated with pregnancy. The malignant form of GTD is referred  as Gestational Trophoblastic Neoplasia (GTN).
CLASSIFICATION: Morphological classification of GTD is less important. Because at present management is largely medical irrespective of histology. Follow-up of patients with GTD again depends on hCG than on histologic diagnosis  (Box  16.6).  Immunohistochemical  and molecular studies are thought to be more important.
Non-gestational trophoblastic disease occurs as a primary choriocarcinoma of the ovary and is probably a teratomatous tumor.

I HYDATIDIFORM MOLE (SYN: VESICULAR MOLE) TYPES:  + Complete  + Incomplete (partial)
The  types  are  categorized  on  the  basis  of  gross morphology, histopathology and karyotype (Table  16.2). However, unless specified, molar pregnancy  relates one with complete mole.
DEFINITION: It is an abnormal condition of the placenta where  there  are  partly  degenerative  and  partly proliferative changes in the young chorionic villi. These result in the formation of clusters of small cysts of varying sizes. Because of its superficial resemblance to hydatid cyst, it is named as hydatidiform mole. It is best regarded as a benign neoplasia of the chorion with malignant potential.
INCIDENCE:  There is wide  range  of geographical and ethnic  variation  of  the  prevalence  of  the  condition.


a   Hydatidiform mole: • Complete  • Partial
11   Gestational Trophoblastic Neoplasia (GTN) 11   Invasive mole
11   Placental site trophoblastic tumor a   Choriocarcinoma
Nonmetastatic disease (confined to the uterus) Metastatic disease:
A.  Low-risk (good prognosis)
•  Disease is present <4 months  duration. •  Initial serum  hCG  level  <40,000 mlU/mL. • Metastasis limited to lung and vagina.
•  No prior chemotherapy.
•  No preceding term  delivery. B.  High-risk (poor prognosis)
• Long duration of disease  (>4 months). •  Initial serum hCG  >40,000  mlU/mL.
•  Brain or liver metastasis.
•  Failure of prior  chemotherapy. •  Following term pregnancy.
• WHO score >7.




The molar pregnancy is common in oriental countries­ Philippines,  China,  Indonesia,  Japan,  India,  Central and Latin America and Africa. The highest incidence is in Philippines being 1 in 80 pregnancies and lowest in European countries 1 in 752 and USA being about  1 in 2,000. The incidence, in India, is about 1 in 400.
ETIOLOGY:  The cause is not definitely known, but it appears to be related to the ovular defect as it sometimes affects one ovum of a twin pregnancy. However, the following factors and hypotheses have been forwarded:
11      Its prevalence is highest in teenage pregnancies and in those women over 35 years of age.
11    The prevalence appears to vary with race and ethnic origin.
11    Faulty nutrition caused by inadequate intake of protein, animal fat could partly explain its prevalence in the oriental countries. Low dietary intake of carotene is associated with increased risk.
11    Disturbed maternal immune mechanisms suggested by-(a)  Rise in gammaglobulin level in absence of hepatic disease.  (b) Increased association with AB blood group which possesses no ABO antibody.
11    Cytogenetic  abnormality:  In  general,  complete moles have a 46,XX karyotype  (85%),  the molar chromosomes are derived entirely from the father. The ovum nucleus may be either absent (empty ovum) or inactivated which has been fertilized by a haploid sperm. It then duplicates its own chromosomes after meiosis. This phenomenon is known as androgenesis. Infrequently, the chromosomal pattern may be 46,XY or45,X.
11    The higher the ratio of paternal-maternal chromo­ somes, the greater is the molar change.  Complete moles show 2:0 paternal/maternal ratio whereas partial mole shows 2:1 ratio.
11    History  of  prior  hydatidiform  mole  increases  the chance of recurrence (1-4%).

I PATHOLOGY OF HYDATIDIFORM MOLE

It is  principally  a  disease  of  the  chorion.  Death  of the  ovum or failure of the embryo to grow is essential to develop complete (classic) hydatidiform mole. The secretion from the hyperplastic cells and transferred substances from the maternal blood accumulate in the stroma of the villi which are devoid of blood vessels. This results in distension of the villi to form small vesicles. The distension may also be due to edema and liquefaction of the stroma. Vesicle fluid is interstitial fluid and is almost similar to ascitic or edema fluid, but rich in hCG.
Naked eye appearance (Fig. 16.18): The mass filling the uterus is made of multiple  chains and clusters of cysts of varying sizes. There is no trace of embryo or the amniotic sac. Hemorrhage, if occurs, takes place in the decidual space.
Chapter 16: Hemorrhage in Early Pregnancy	Im· -
















Fig. 16.18:  Hydatidiform mole showing clusters of vesicles of
varying sizes (see the arrows).

Mic roscopic  appearance:  The basic findings are-(l) There is marked proliferation of the syncytial and  cytotrophoblastic  epithelium.  (2)  Marked thinning  of  the  stromal  tissue  due  to  hydropic degeneration.  (3)  There is absence of blood vessels in the villi which seems primary rather than due to pressure atrophy. ( 4) The villous pattern is distinctly maintained.
Ovarian changes:  Bilateral lutein  cysts  are  present in about 50%. These are due to excessive production of chorionic gonadotropin and they are also observed in multiple pregnancy. These regress spontaneously within 2  months  after  expulsion  of  mole.  The  contained fluid is rich in chorionic gonadotropin. It also contains estrogen and progesterone.

I CLINICAL FEATURES

Age and parity: It is prevalent amongst teenaged and elderly patients with high parity (Box 16.7). The patient gives history of amenorrhea of 8-12 weeks with initial features suggestive of normal pregnancy but subsequently presents  with  the  following  manifestations  (often confused with abortion).
SYMPTOMS
11    Vaginal  bleeding:  Vaginal  bleeding  is  the  most common presentation  (90%).  Often the symptoms mimic an incomplete or threatened abortion. The blood may be mixed with a gelatinous fluid from ruptured cysts giving the appearance of discharge 'white currant in red currant juice'.
11    Varying degree of lower abdominal pain may be due to-(a) overstretching of the uterus, (b) concealed hemorrhage, (c) rarely perforation of the uterus by the invasive mole, (d) infection or (e) uterine contractions to expel out the contents.
11    Constitutional symptoms: (a) The patient becomes sick  without  any  apparent reason.  (b)  Vomiting

of   pregnancy   becomes   excessive   to   the   stage of hyperemesis in 15% cases. It is probably related to excess chorionic gonadotropin. (c) Breathlessness due to pulmonary embolization of the trophoblastic cells (2%). (d) Thyrotoxic features of tremors or tachycardia are present on occasion (2%). It is probably due to increased chorionic thyrotropin.
11    Expulsion  of  grape-like  vesicles  per  vaginam is diagnostic of vesicular mole. Actually,  in approxi­ mately 50% of cases, the mole is not suspected until it is expelled in part or whole.
a  History of quickening is absent.
SIGNS
11    Features suggestive of early months of pregnancy are evident.
11    The patient looks more ill than can be accounted for.
11    Pallor  is  present  and  may  be  unusually  out  of proportion to the visible blood loss. This may be due to concealed hemorrhage.  It is mostly due to iron deficiency but may be megaloblastic due to folic acid deficiency.
11    Features of pre-eclampsia  (hypertension,  edema and/or proteinuria) are present in about 50%. On rare occasion, convulsion may occur.
Per abdomen:
11    The size of the uterus is more than that expected for the period of amenorrhea in 70%, corresponds with  the period of amenorrhea in 20% and smaller than the period of amenorrhea in 10%. The frequent finding of undue enlargement of the uterus is due to exuberant growth of the vesicles and the concealed hemorrhage.
11    The feel of the uterus is firm elastic (doughy). This is due to the absence of the amniotic fluid sac.
11    Fetal parts are not felt,  nor any fetal movements. External ballottement cannot be elicited.
11    Absence  of  fetal  heart  sound  which  cannot  be detected even by the Doppler effect cardioscope.
The negative abdominal signs are of value when these signs should have been present depending on the size of the uterus presented in the particular case.


•  Abnormal vaginal bleeding. •  Lower abdominal pain.
♦   Hyperemesis gravidarum.
♦   Features of early onset pre-eclampsia <20 weeks. ♦   Uterus> dates (50%).
♦   Absent fetal parts and FHS.
♦   Expulsion of vesicular tissues (Fig. 16.18). ♦   Theca lutein cyst of ovaries (25%) >6 cm. ♦   Hyperthyroidism (rare).
♦   Serum hCG>100,000 mlU/mL. ♦   USG-snowstorm appearance.
-ID Chapter 16: Hemorrhage in Early Pregnancy

Vaginal examination:
ll    Internal ballottement cannot be elicited.
11    Unilateral or bilateral enlargement (theca lutein cyst) of the ovary may be palpable in 25-50% of cases. The enlarged ovary may not be palpable due to the enlarged uterus.
11    Finding  of  vesicles  in  the  vaginal  discharge  is pathognomonic of hydatidiform mole.
11    If the cervical os is open, instead of the membranes, blood clot or the vesicles may be felt.

Investigations:
♦   Full blood count, ABO and Rh grouping.
♦   Hepatic, renal and thyroid function tests are carried out.
♦   Sonography: Complete mole appears as an echogenic mass  with  many  anechoic   cystitic   spaces.   There is neither  the fetus  nor  the  amniotic sac.  Fetus  is present in partial mole. Characteristic feature of molar pregnancy is 'snowstorm' appearance {Fig. 16.19). Sometimes confusion arises with the missed abortion, partial mole or the degenerated fibroid.
♦   Quantitative estimation of chorionic gonadotropin: High hCG  titer  in urine  (positive pregnancy test) diluted up to 1 in 200 to 1 in 500 beyond 100 days of gestation is very much suggestive. Rapidly increasing value  of  serum  hCG  (hCG  >100,000  mlU/mL),  is usual with  molar  pregnancies.  Normal  pregnancy value reaches a peak at about 10-14 weeks and rarely it is more than 100,000 mlU/mL.  Serum hCG value greater  than 2 Multiples of the Median (MOM) for corresponding gestational age is of value.
♦   Chest radiograph should  also be carried out as a routine for evidence of pulmonary embolization even in benign mole.
♦   CT and MRI:  Routine use of computed tomography or magnetic resonance imaging for diagnosis is not recommended.
















Fig. 16.19: USG showing snowstorm appearance of hydatidiform mole.
















Fig.  16.20:  Histological section of  hydatidiform  mole  showing hydropic  degeneration  of  the  villous  stroma  with  absence  of blood vessels and trophoblastic proliferation.
Courtesy: Dr SK Dutta

♦   Definitive   diagnosis   is   made   by   histological examination of the products of conception (Fig. 16.20).
DIFFERENTIAL  DIAGNOSIS:  The  following  conditions are often confused with molar pregnancy: Estimation of serum hCG and ultrasonography are diagnostic.
•   Threatened abortion
•   Fibroid or ovarian tumor with pregnancy •   Multiple pregnancy
Twin pregnancy with one normal fetus and placenta and the other with complete mole is differentiated from partial mole by cytogenetic and high resolution USG studies (Figs. 16.23A and B).
I COMPLICATIONS OF MOLAR PREGNANCY
Immediate: (1) Hemorrhage and shock-the causes of hemorrhage are: (a) Separation of the vesicles from its attachment to the decidua.  The hemorrhage may be concealed or revealed.  {b) Massive intraperitoneal hemorrhage which may be the first feature of a perforating mole.  (c)  During  evacuation of  the  mole  due  to-(i) atonic uterus or (ii) uterine injury.
(2)  Sepsis: The increased risk of sepsis is due to: (a) As there are no protective membranes, the vaginal organisms  can  creep  up  into  the  uterine  cavity.  (b) Presence  of  degenerated  vesicles,  sloughing decidua and old blood favors nidation of bacterial growth.  (c) Increased operative interference.
(3) Perforation of the uterus: The uterus may be injured due to: (a) Perforating mole-which may produce massive intraperitoneal hemorrhage. (b) During vaginal evacuation especially by conventional (D & E) method or during curettage following suction evacuation.
( 4) Pre-eclampsia with convulsion on rare occasion.
(5) Acute pulmonary insuficiency due to pulmonary embolization of the trophoblastic cells with or without
Chapter 16: Hemorrhage in Early Pregnancy	m

villi stroma. Symptoms usually begins within 4-6 hours following evacuation.
(6) Coagulation failure due to pulmonary embolization of trophoblastic cells as they cause fibrin and platelets deposition within the vascular tree (p. 583).
Late: The development of choriocarcinoma following hydatidiform mole ranges between 2-10%. The known risk factors are recorded in the box which are more likely to be associated with the malignant change.
PROGNOSIS:  Immediate  risk  from  hemorrhage  and sepsis are markedly diminished due to early diagnosis, blood  transfusion  and  treatment.  About  15-20%  of complete moles progress to persistent GTD where there is a plateau or re-elevation of the hCG level. In about 5% cases, metastatic disease develops. The risk ofrecurrence of hydatidiform mole in future pregnancy is about 1-4%. However, chance of fetal malformation is not increased following chemotherapy.  The improvement and long term  prognosis  may  be  attributed  to  the  following factors:  (i)  Recognition of high-risk factors  related to choriocarcinoma.   (ii)  Careful  follow-up  with  serum  -hCG. (iii) Use of cytotoxic drug at the optimum time and in the right case.
I MANAGEMENT

With the use of ultrasonography and sensitive hCG testing, diagnosis is made early in majority of the cases.
Women  may  present  with  the  features  of  severe anemia, pre-eclampsia, hyperthyroidism or hyperemesis gravidarum.
The principles in the management are:
♦    Suction Evacuation (SE) of the uterus as early as the diagnosis is made.
♦    Supportive  therapy:  Correction  of  anemia,  other medical complications and infection.
♦  Counseling for regular follow-up (p. 187).
The patients are grouped into two (Flowchart 16.4):
■   Group A:  The  mole  is  in  process  of expulsion  g. 16.21)-less common.
■   Group B: The uterus remains inert (early diagnosis with ultrasonography).

SUPPORTIVE THERAPY: The patient usually presents with variable amount of bleeding and often they are anemic and associated with infection: (i) N infusion with Ringer's solution is started.  (ii)  Blood transfusion is given if the patient is anemic. (iii) Parenteral antibiotic is given if there is associated infection.  (iv) Blood is kept reserved during the evacuation as there is risk of hemorrhage.
DEFINITIVE MANAGEMENT: Suction Evacuation (SE) is the method of treatment. It is safe, rapid and effective in almost all cases. Suction evacuation can safely be done even when the uterus is of 28 weeks of gestation.

■   Group A:  Cervix is favorable-(a)  The preferred method is suction evacuation. A negative pressure is applied up to 200-250 mm Hg. The procedure can be performed under diazepam sedation or general anesthesia.
(b) Alternatively, conventional dilatation of the cervix followed  by  evacuation  is  done.  During  evacuation procedure patient should ideally be monitored by pulse oximeter (oxygen saturation). Intraoperative USG may done to ensure complete uterine evacuation.  500 mL Ringer's solution N infusion is set up. Risk of hemorrhage is high especially when the uterus is large. Senior surgeon should  be  present  during  the  SE  procedure.  Use  of oxytocin helps the expulsion of moles and reduces blood loss but its routine use is not recommended due to the risks of embolization (see below).
(c) Digital exploration and removal of the mole by ovum forceps under general anesthesia may also be an alternative procedure.
After the evacuation is completed, methergine-0.2 mg is given intramuscularly.
■   Group B: Cervix is tubular and closed-prior slow dilatation of the cervix is done by introducing laminaria tent followed by suction and evacuation. Alternatively,
vaginal misoprostol (PGE1) 400 mg, 3 hours before surgery may be used.
Complications of vaginal evacuation: Apart from the injury to the uterus, hemorrhage and shock, there are two more rare but fatal complications-(1) Acute pulmonary insufficiency due to pulmonary embolization of the trophoblastic cells. Symptoms of acute chest pain, pulmonary edema, tachycardia, tachypnea and dyspnea develop about 4-6 hours following evacuation. Medical induction (oxytocin infusion) before evacuation may increase the
risk of pulmonary insufficiency (RCOG). Arterial P02 is monitored. Patient may need ventilatory assistance and intensive care unit
management. (2) Trophoblast-tissues are deported into the lungs during the process of evacuation. Despite this, development

















Fig. 16.21: Hydatidiform mole in the process of expulsion showing clusters of vesicles of varying sizes.
Courtesy: Dr Subrata Bhattacharya, Silchar
II Chapter 16: Hemorrhage in Early Pregnancy
Flowchart 16.4:  Scheme of  management  of hydatidiform  mole.
Management



In process of expulsion

• IV infusion ( crystalloids) • Blood transfusion

Accelerate evacuation


Uterus inert

• To correct anemia by blood transfusion
• To keep blood during evacuation



Suction evacuation ±
Oxytocin drip


Gentle currettage following evacuation in selected cases only


■ Patient young
■ Desirous of child


Evacuation


■ Age >35
■  Family completed
■  Perforating H mole
l
Hysterectomy (selective)








l
Cervix-favorable
l

Suction evacuation +
Oxytocin drip


Vaginal (preferred)
l


l
Cervix-unfavorable
l

Slow dilatation of the cervix (laminaria tent/PGE,)
l

Suction evacuation ± Oxytocin

Abdominal hysterotomy (rarely)
■ Cervix unfavorable ■ Bleeding PV++




Currettage in selected cases only


Prophylactic cytotoxic therapy (controversial)

■ Follow-up as a routine (at least for 1 year) ■ Monitor maternal serum/urine hCG



hCG level plateaus or re-elevation	hCG level returns to normal (4-6 weeks)
l
l
l

Exclude new pregnancy	Monthly follow-up X 6, then every 2-3 months for 6 months

Evaluate for persistent trophoblastic disease
(X-ray chest, CT/MRI for brain, liver, chest, pelvis, serum hCG)



of persistent trophoblastic disease or choriocarcinoma has not been observed as yet.
•   Hysterectomy is indicated in: (i) Patients with age over 35. (ii) Patient completed her family irrespective of age. (iii) Uncontrolled hemorrhage or perforation during surgical evacuation. Hysterectomy reduces the risk of GTN by five-fold.

•   Hysterotomy is rarely done these days. It may be done in cases with-(i) profuse vaginal bleeding, (ii) cervix is unfavorable for immediate vaginal evacuation and (iii) accidental perforation of the uterus during surgical evacuation.
It should be remembered that following hysterectomy, persistent GTD is observed in 3-5% cases. As such, it does
Chapter 16: Hemorrhage in Early Pregnancy    .,

not eliminate the necessity of follow-up. The enlarged ovaries (theca lutein cysts) found during operation should be left undisturbed as they will regress following removal of mole. But, if complication arises, like torsion, rupture or infarction, they should be removed. The uterus following hysterectomy should  be  sent  for  histopathological examination.
Following evacuation anti-D immunoglobulin should be given to the Rh-negative nonimmunized patient.

PLACE   OF   CURETTAGE  FOLLOWING   VAGINAL   EVACUATION: Routine curettage is not commonly recommended. It is done in selected cases with persistent vaginal bleeding (persistent GTN). Gentle curettage may be done 5-7 days following evacuation. At this time the uterine wall gets thicker, firmer and the cavity becomes smaller so that effective curettage can be done without risk of damaging the uterus. The objective of curettage is to remove  the  necrosed  decidua  and  the  attached  vesicles  so as  to accelerate involution and to reduce the irregular bleeding. The materials should be sent for histology to note the degree of  trophoblastic  hyperplasia  and  to  see  whether  the  villous structure is present or not.
FOLLOW-UP:   Routine   follow-up   is   mandatory   for all  cases  for  at  least 6  months.  The  occurrence  of choriocarcinoma is mostly confined to this period.  The prime objective is to diagnose persistent trophoblastic disease (15-20%) that is considered malignant. However, hCG levels following evacuation should regress to normal within 3 months of time.
Intervals:  Initially,  the  checkup  should  be  at  an interval of one week till the serum hCG level becomes negative.  This  usually happens  by 4-8 weeks.  Once negative within 56 days, the patient is followed up at every one month interval for 6 months. The patient must not become pregnant during the period of follow-up.
Post evacuation: Follow-up protocols: (i) History and clinical examination and (ii) hCG assay.
Methods employed in each visit: (1) Enquire about relevant  symptoms  like  irregular  vaginal  bleeding, persistent cough, breathlessness or hemoptysis.
(2)  Abdominovaginal  examination  to  note:  {i) involution  of  the  uterus,  (ii)  ovarian  size  and  {iii) malignant  deposit  if  any,  in  the  anterior  vaginal  wall. The lutein cysts usually regress within 2 months. Pelvic examination or USG evaluation is done after one week of molar evacuation.
(3)  Investigations:  (i)  Detection  of serum  P-hCG assays are carried out at every visit. The molecule hCG (glycoprotein)  has  structural  heterogeneity.  It  exists in different isoforms. Therefore,  tests should include assay for all isoforms of hCG. When pre-evacuation chest radiogram is normal, it is repeated only when the hCG titer plateaus or rises.
PROPHYLACTIC CHEMOTHERAPY: About 80% of patients undergo   spontaneous   remission.   Sensitive   P-hCG assay can identify the women that develop malignancy.


•  Patient's age 2c40 or <20 years irrespective of parity. •  Parity 2c3. Age is more important than the parity.
♦   Serum hCG > 100,000 mlU/mL. •  Uterine size >20 weeks.
♦   Previous history of molar pregnancy.
♦   Theca lutein cysts-large (>6 cm diameter).

Moreover, the drugs used are toxic. These drugs in young females increase the risk of premature ovarian failure and menopause. So it is not appropriate to treat all patients with prophylactic chemotherapy as a routine.
However,  chemotherapy is  used  in the following circumstances: Risk of malignancy in cases with  com­ plete   mole  is  15-20%.   The   risk   in   partial   mole is 1-5%.  The diagnostic criteria for postmolar GTN    has been described (p. 189). The other high risk  factors are described in p. 187 (Box 16.8). Single agent:  Chemo­ therapy is started for low risk women.
Regimes: Methotrexate, 1 mg/kg/day IV or IM is given on days 1, 3, 5 and 7 with folinic acid 0.1 mg/kg IM on days 2, 4, 6 and 8. It is to be repeated every 7 days. A total three courses are given. P-hCG  level should  decrease  by  at  least  15%,  4-7  days  after methotrexate. Alternatively, intravenous actinomycin D 12 mg/ kg body weight daily for 5 days may be given. It is less toxic than methotrexate (Read more Dutta's Textbook ofGynecology, Ch. 24).
CONTRACEPTIVE ADVICE: Once serum P-hCG remains undetectable for another 6 months following the initial negative result, monitoring is discontinued. She is allowed to become pregnant. But pregnancy is delayed at least up to 1 year for cases with gestational trophoblastic neoplasia and up to 2 years if there is metastasis.
Use of contraception: IUD is contraindicated, because of its frequent association of irregular vaginal bleeding. This often confuses with choriocarcinoma. Risk of uterine perforation  is  also high.  Combined oral  pills  can  be used after the hCG value has become normal. Injection DMPA or progestin implant can be used safely (p. 510). Barrier method of  contraception  can  also  be  used. Surgical sterilization is another alternative when she has completed her family.
Unfavorable manifestations: (1) Persistent ill health. (2) Irregular vaginal bleeding or continuing amenorrhea. (3) Appearance  of respiratory  symptoms.  (4) Subin­ volution.  (5)  Appearance of  secondary metastasis in the  vagina.  (6)  Chest  radiograph  showing  positive finding of' cannon  ball' shadow. {7) hCG titers remain elevated or there is re-elevation after a negative report. All these are high-risks factors for GTN. hCG levels should be  checked 6 weeks   after the end of any pregnancy, subsequent to a molar one.

PARTIAL OR INCOMPLETE MOLE
In partial hydatidiform mole, the affection of the chorionic villi is focal. There is a fetus or at least an amniotic sac.
!
ia	Chapter 16: Hemorrhage in Early Pregnancy
ll






the patient should be warned about the risks involved to the fetus if pregnancy is continued.
Post-termination follow-up protocol should be the same as outlined in complete mole. As the chance of malignancy is much less, the follow-up for 3-6 months is to be continued after hCG level returns to normal.
TWIN   PREGNANCY-COEXISTENT   MOLAR    PREGNANCY   AND A NORMAL FETUS: Coexistent molar pregnancy with a normal fetus is relatively rare (1 in 22,000 to 1 in 1,00,000 pregnancies). This patient (Figs. 16.23A and B), age 34-year-old lady, P-0, G-4, A-3, L-0, conceived following IVF and ET.  Pregnancy ended in miscarriage at 18 weeks gestation due to the complication of excessive  hemorrhage.  Medical complications of such a twin pregnancy, including hyperemesis gravidarum, hyperthyroidism, PIH  and  hemorrhage  are increased.  These  patients  have  an increased  risk  of  developing  postmolar  GTN  and  metastatic disease.






Fig. 16.22: Partial  mole with a  stillborn  baby. Courtesy: Dr Chandana Das, Professor, NR5 Medical College, Kolkata

The karyotype is triploid either 69,XXY or 69,YY with one maternal but usually two paternal haploid chromosomes. Microscopic examination of the dilated chorionic villi shows predominant hyperplasia of the syncytiotrophoblast and presence of fetal blood vessels with fetal red blood cells. The fetus, if present, dies in early first trimester. Rarely, the baby may be born which is growth retarded with multisystem abnormalities (Fig.16.22).
The clinical picture does not differ markedly from complete mole and too often confused with threatened or missed abortion (Table 16.2). The hCG titer is not markedly raised. With wider use of sonography, more and more cases are being revealed. In partial mole, uterus is generally not large for dates and malignant potential is very low.
Once the diagnosis is made and the fetus is not alive, termination of pregnancy is to be done. Even if the fetus is alive,

PLACENTAL SITE TROPHOBLASTIC TUMOR (PSTT)

It is a rare histological diagnosis. Syncytiotrophoblastic cells  are  generally  absent.  So  there  is  persistent  low level  of  serum  or  urinary  hCG.  The  tumor  arises from the   intermediate   trophoblasts  of   the   placental bed and is composed mainly of cytotrophoblastic cells. Patient presents with vaginal bleeding. Local invasion into  the  myometrium  and  lymphatics  occurs.  PSTT is not responsive to chemotherapy. Hysterectomy is the preferred treatment.

PERSISTENT GESTATIONAL TROPHOBLASTIC NEOPLASIA

DEFINITION:  Persistent GTD  is defined  where  there  is persistence  of  trophoblastic  activity  as  evidenced  by clinical,  imaging,  pathological and/or  hormonal study following initial treatment. This may be following treatment of hydatidiform mole,  invasive  mole,  choriocarcinoma


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